C10 heterosubstituted acetate taxanes

ABSTRACT

Taxanes having a heterosubstituted acetate substituent at C(10), a hydroxy substituent at C(7), and a range of C(2), C(9), C(14), and side chain substituents.

REFERENCE TO RELATED APPLICATION

[0001] This application claims priority from U.S. provisionalapplication Serial No. 60/179,669, filed on Feb. 2, 2000.

BACKGROUND OF THE INVENTION

[0002] The present invention is directed to novel taxanes which haveexceptional utility as antitumor agents.

[0003] The taxane family of terpenes, of which baccatin III and taxolare members, has been the subject of considerable interest in both thebiological and chemical arts. Taxol itself is employed as a cancerchemotherapeutic agent and possesses a broad range of tumor-inhibitingactivity. Taxol has a 2'R, 3'S configuration and the followingstructural formula:

[0004] wherein Ac is acetyl.

[0005] Colin et al. reported in U.S. Pat. No. 4,814,470 that certaintaxol analogs have an activity significantly greater than that of taxol.One of these analogs, commonly referred to as docetaxel, has thefollowing structural formula:

[0006] Although taxol and docetaxel are useful chemotherapeutic agents,there are limitations on their effectiveness, including limited efficacyagainst certain types of cancers and toxicity to subjects whenadministered at various doses. Accordingly, a need remains foradditional chemotherapeutic agents with improved efficacy and lesstoxicity.

SUMMARY OF THE INVENTION

[0007] Among the objects of the present invention, therefore, is theprovision of taxanes which compare favorably to taxol and docetaxel withrespect to efficacy as anti-tumor agents and with respect to toxicity.In general, these taxanes possess a heterosubstituted acetatesubstituent at C-10, a hydroxy substituent at C-7 and a range of C-3′substituents.

[0008] Briefly, therefore, the present invention is directed to thetaxane composition, per se, to pharmaceutical compositions comprisingthe taxane and a pharmaceutically acceptable carrier, and to methods ofadministration.

[0009] Other objects and features of this invention will be in partapparent and in part pointed out hereinafter.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] In one embodiment of the present invention, the taxanes of thepresent invention correspond to structure (1):

[0011] wherein

[0012] R₂ is acyloxy;

[0013] R₇ is hydroxy;

[0014] R₉ is keto, hydroxy, or acyloxy;

[0015] R₁₀ is heterosubstituted acetate;

[0016] R₁₄ is hydrido or hydroxy;

[0017] X₃ is substituted or unsubstituted alkyl, alkenyl, alkynyl,phenyl or heterocyclo;

[0018] X₅ is —COX₁₀, —COOX₁₀, or —CONHX₁₀;

[0019] X₁₀ is hydrocarbyl, substituted hydrocarbyl, or heterocyclo;

[0020] Ac is acetyl; and

[0021] R₇, R₉, and R₁₀ independently have the alpha or betastereochemical configuration.

[0022] In one embodiment, R₂ is an ester (R_(2a)C(O)O—), a carbamate(R_(2a)R_(2b)NC(O)O—), a carbonate (R_(2a)OC(O)O—), or a thiocarbamate(R_(2a)SC(O)O—) wherein R_(2a) and R_(2b) are independently hydrogen,hydrocarbyl, substituted hydrocarbyl or heterocyclo. In a preferredembodiment, R₂ is an ester (R_(2a)C(O)O—), wherein R_(2a) is aryl orheteroaromatic. In another preferred embodiment, R₂ is an ester(R_(2a)C(O)O—), wherein R_(2a)is substituted or unsubstituted phenyl,furyl, thienyl, or pyridyl. In one particularly preferred embodiment, R₂is benzoyloxy.

[0023] While R₉ is keto in one embodiment of the present invention, inother embodiments R₉ may have the alpha or beta stereochemicalconfiguration, preferably the beta stereochemical configuration, and maybe, for example, α- or β-hydroxy or α- or β-acyloxy. For example, whenR₉ is acyloxy, it may be an ester (R_(9a)C(O)O—), a carbamate(R_(9a)R_(9b)NC(O)O—), a carbonate (R_(9a)OC(O)O—), or a thiocarbamate(R_(9a)SC(O)O—) wherein R_(9a) and R_(9b) are independently hydrogen,hydrocarbyl, substituted hydrocarbyl or heterocyclo. If R₉ is an ester(R_(9a)C(O)O—), R_(9a) is substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstituted arylor substituted or unsubstituted heteroaromatic. Still more preferably,R₉ is an ester (R_(9a)C(O)O—), wherein R_(9a) is substituted orunsubstituted phenyl, substituted or unsubstituted furyl, substituted orunsubstituted thienyl, or substituted or unsubstituted pyridyl. In oneembodiment R₉ is (R_(9a)C(O)O—) wherein R_(9a) is methyl, ethyl, propyl(straight, branched or cyclic), butyl (straight, branched or cyclic),pentyl, (straight, branched or cyclic), or hexyl (straight, branched orcyclic). In another embodiment R₉ is (R_(9a)C(O)O—) wherein R_(9a) issubstituted methyl, substituted ethyl, substituted propyl (straight,branched or cyclic), substituted butyl (straight, branched or cyclic),substituted pentyl, (straight, branched or cyclic), or substituted hexyl(straight, branched or cyclic) wherein the substituent(s) is/areselected from the group consisting of heterocyclo, alkoxy, alkenoxy,alkynoxy, aryloxy, hydroxy, protected hydroxy, keto, acyloxy, nitro,amino, amido, thiol, ketal, acetal, ester and ether moieties, but notphosphorous containing moieties.

[0024] In one embodiment, R₁₀ is R_(10a) C(O)O— wherein R_(10a) isheterosubstituted methyl, said heterosubstituted methyl moiety lacking acarbon atom which is in the beta position relative to the carbon atom ofwhich R_(10a) is a substituent. The heterosubstituted methyl iscovalently bonded to at least one heteroatom and optionally withhydrogen, the heteroatom being, for example, a nitrogen, oxygen,silicon, phosphorous, boron, sulfur, or halogen atom. The heteroatommay, in turn, be substituted with other atoms to form a heterocyclo,alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, oxy,acyloxy, nitro, amino, amido, thiol, ketals, acetals, esters or ethermoiety. Exemplary R₁₀ substituents include R_(10a)COO— wherein R_(10a)is chloromethyl, hydroxymethyl, methoxymethyl, ethoxymethyl,acetoxymethyl, acyloxymethyl, or methylthiomethyl.

[0025] Exemplary X₃ substituents include substituted or unsubstituted C₂to C₈ alkyl, substituted or unsubstituted C₂ to C₈ alkenyl, substitutedor unsubstituted C₂ to C₈ alkynyl, substituted or unsubstitutedheteroaromatics containing 5 or 6 ring atoms, and substituted orunsubstituted phenyl. Exemplary preferred X₃ substituents includesubstituted or unsubstituted ethyl, propyl, butyl, cyclopropyl,cyclobutyl, cyclohexyl, isobutenyl, furyl, thienyl, and pyridyl.

[0026] Exemplary X₅ substituents include —COX₁₀, —COOX₁₀ or —CONHX₁₀wherein X₁₀ is substituted or unsubstituted alkyl, alkenyl, phenyl orheteroaromatic. Exemplary preferred X₅ substituents include —COX₁₀,—COOX₁₀ or —CONHX₁₀ wherein X₁₀ is (i) substituted or unsubstituted C₁to C₈ alkyl such as substituted or unsubstituted methyl, ethyl, propyl(straight, branched or cyclic), butyl (straight, branched or cyclic),pentyl (straight, branched or cyclic), or hexyl (straight, branched orcyclic); (ii) substituted or unsubstituted C₂ to C₈ alkenyl such assubstituted or unsubstituted ethenyl, propenyl (straight, branched orcyclic), butenyl (straight, branched or cyclic), pentenyl (straight,branched or cyclic) or hexenyl (straight, branched or cyclic); (iii)substituted or unsubstituted C₂ to C₈ alkynyl such as substituted orunsubstituted ethynyl, propynyl (straight or branched), butynyl(straight or branched), pentynyl (straight or branched), or hexynyl(straight or branched); (iv) substituted or unsubstituted phenyl, or (v)substituted or unsubstituted heteroaromatic such as furyl, thienyl, orpyridyl, wherein the substituent(s) is/are selected from the groupconsisting of heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy,protected hydroxy, keto, acyloxy, nitro, amino, amido, thiol, ketal,acetal, ester and ether moieties, but not phosphorous containingmoieties.

[0027] In one embodiment of the present invention, the taxanecorresponds to structure 1, X₅ is —COX₁₀ wherein X₁₀ is phenyl or—COOX₁₀ wherein X₁₀ is t-butoxycarbonyl, and R₁₀ is R_(10a)C(O)O—wherein R_(10a) is alkoxymethyl, preferably methoxymethyl orethoxymethyl. In another embodiment of the present invention the taxanecorresponds to structure 1, X₅ is —COX₁₀ wherein X₁₀ is phenyl or—COOX₁₀ wherein X₁₀ is t-butoxycarbonyl, and R₁₀ is R_(10a)C(O)O—wherein R_(10a) is acyloxymethyl, preferably acetoxymethyl.

[0028] In another embodiment of the present invention, the taxanecorresponds to structure 1, X₅ is —COX₁₀ wherein X₁₀ is phenyl or—COOX₁₀ wherein X₁₀ is t-butoxycarbonyl, R₁₀ is R_(10a)C(O)O— whereinR_(10a) is alkoxymethyl such as methoxymethyl or ethoxymethyl, oraryloxymethyl such as phenoxymethyl, and X₃ is heterocyclo. In anotherembodiment of the present invention the taxane corresponds to structure1, X₅ is —COX₁₀ wherein X₁₀ is phenyl or —COOX₁₀ wherein X₁₀ ist-butoxycarbonyl, and R₁₀ is R_(10a)C(O)O— wherein R_(10a) isacyloxymethyl, preferably acetoxymethyl, and X₃ is heterocyclo.

[0029] In one preferred embodiment of the present invention, the taxanesof the present invention correspond to structure (2):

[0030] wherein

[0031] R₇ is hydroxy;

[0032] R₁₀ is heterosubstituted acetate;

[0033] X₃ is substituted or unsubstituted alkyl, alkenyl, alkynyl, orheterocyclo, wherein alkyl comprises at least two carbon atoms;

[0034] X₅ is —COX₁₀, —COOX₁₀, or —CONHX₁₀; and

[0035] X₁₀ is hydrocarbyl, substituted hydrocarbyl, or heterocyclo.

[0036] For example, in this preferred embodiment in which the taxanecorresponds to structure (2), R₁₀ is R_(10a)COO— wherein R_(10a) isheterosubstituted methyl, more preferably heterosubstituted methylwherein the heterosubsituents are selected from the group consisting ofnitrogen, oxygen, silicon, phosphorous, boron, sulfur, or halogen atoms,still more preferably heterosubstituted methyl wherein theheterosubstituent is alkoxy or acyloxy. While R_(10a) is selected fromamong these, in one embodiment X₃ is selected from substituted orunsubstituted alkyl, alkenyl, phenyl or heterocyclo, more preferablysubstituted or unsubstituted alkenyl, phenyl or heterocyclo, still morepreferably substituted or unsubstituted phenyl or heterocyclo, and stillmore preferably heterocyclo such as furyl, thienyl or pyridyl. WhileR_(10a) and X₃ are selected from among these, in one embodiment X₅ isselected from —COX₁₀ wherein X₁₀ is phenyl, alkyl or heterocyclo, morepreferably phenyl. Alternatively, while R_(10a) and X₃ are selected fromamong these, in one embodiment X₅ is selected from —COX₁₀ wherein X₁₀ isphenyl, alkyl or heterocyclo, more preferably phenyl, or X₅ is —COOX₁₀wherein X₁₀ is alkyl, preferably t-butyl. Among the more preferredembodiments, therefore, are taxanes corresponding to structure 2 inwhich (i) X₅ is —COOX₁₀ wherein X₁₀ is tert-butyl or X₅ is —COX₁₀wherein X₁₀ is phenyl, (ii) X₃ is substituted or unsubstitutedcycloalkyl, alkenyl, phenyl or heterocyclo, more preferably substitutedor unsubstituted isobutenyl, phenyl, furyl, thienyl, or pyridyl, stillmore preferably unsubstituted isobutenyl, furyl, thienyl or pyridyl, and(iii) R₁₀ is alkoxyacetyl aryloxyacetyl, or acyloxyacetyl.

[0037] Taxanes having the general formula 1 may be obtained by treatmentof a b-lactam with an alkoxide having the taxane tetracyclic nucleus anda C-13 metallic oxide substituent to form compounds having a b-amidoester substituent at C-13 (as described more fully in Holton U.S. Pat.No. 5,466,834), followed by removal of the hydroxy protecting groups.The β-lactam has the following structural formula (3):

[0038] wherein P₂ is a hydroxy protecting group and X₃ and X₅ are aspreviously defined and the alkoxide has the structural formula (4):

[0039] wherein M is a metal or ammonium, P₇ is a hydroxy protectinggroup and R₁₀ is as previously defined. The alkoxide may be preparedfrom 10-deacetylbaccatin III by selective esterification of the C-10hydroxyl group and then protection of the C-7 hydroxyl group (asdescribed more fully in Holton et al., PCT Patent Application WO99/09021) followed by treatment with a metallic amide.

[0040] Alternatively, taxanes having the general formula 1 may beobtained by treatment of a b-lactam with an alkoxide having the taxanetetracyclic nucleus and a C-13 metallic oxide substituent to formcompounds having a b-amido ester substituent at C-13 (as described morefully in Holton U.S. Pat. No. 5,466,834), followed by selectivedeprotection of the C(10) hydroxy group and reaction with an acylatingagent such as an alkoxyacetyl halide.

[0041] Derivatives of 10-deacetylbaccatin III having alternativesubstituents at C(2), C(9) and C(14) and processes for their preparationare known in the art. Taxane derivatives having acyloxy substituentsother than benzoyloxy at C(2) may be prepared, for example, as describedin Holton et al., U.S. Pat. No. 5,728,725 or Kingston et al., U.S. Pat.No. 6,002,023. Taxanes having acyloxy or hydroxy substituents at C(9) inplace of keto may be prepared, for example as described in Holton etal., U.S. Pat. No. 6,011,056 or Gunawardana et al., U.S. Pat. No.5,352,806. Taxanes having a beta hydroxy substituent at C(14) may beprepared from naturally occurring 14-hydroxy-10-deacetylbaccatin III.

[0042] Processes for the preparation and resolution of the β-lactamstarting material are generally well known. For example, the β-lactammay be prepared as described in Holton, U.S. Pat. No. 5,430,160 and theresulting enatiomeric mixtures of β-lactams may be resolved by astereoselective hydrolysis using a lipase or enzyme as described, forexample, in Patel, U.S. Pat. No. 5,879,929 Patel U.S. Pat. No. 5,567,614or a liver homogenate as described, for example, in PCT PatentApplication No. 00/41204. In a preferred embodiment in which theβ-lactam is furyl substituted at the C(4) position, the β-lactam can beprepared as illustrated in the following reaction scheme:

[0043] wherein Ac is acetyl, NEt₃ is triethylamine, CAN is cericammonium nitrate, and p-TsOH is p-toluenesulfonic acid. The beef liverresolution may be carried out, for example, by combining the enatiomericβ-lactam mixture with a beef liver suspension (prepared, for example, byadding 20 g of frozen beef liver to a blender and then adding a pH 8buffer to make a total volume of 1 L).

[0044] Compounds of formula 1 of the instant invention are useful forinhibiting tumor growth in mammals including humans and are preferablyadministered in the form of a pharmaceutical composition comprising aneffective antitumor amount of a compound of the instant invention incombination with at least one pharmaceutically or pharmacologicallyacceptable carrier. The carrier, also known in the art as an excipient,vehicle, auxiliary, adjuvant, or diluent, is any substance which ispharmaceutically inert, confers a suitable consistency or form to thecomposition, and does not diminish the therapeutic efficacy of theantitumor compounds. The carrier is “pharmaceutically orpharmacologically acceptable” if it does not produce an adverse,allergic or other untoward reaction when administered to a mammal orhuman, as appropriate.

[0045] The pharmaceutical compositions containing the antitumorcompounds of the present invention may be formulated in any conventionalmanner. Proper formulation is dependent upon the route of administrationchosen. The compositions of the invention can be formulated for anyroute of administration so long as the target tissue is available viathat route. Suitable routes of administration include, but are notlimited to, oral, parenteral (e.g., intravenous, intraarterial,subcutaneous, rectal, subcutaneous, intramuscular, intraorbital,intracapsular, intraspinal, intraperitoneal, or intrasternal), topical(nasal, transdermal, intraocular), intravesical, intrathecal, enteral,pulmonary, intralymphatic, intracavital, vaginal, transurethral,intradermal, aural, intramammary, buccal, orthotopic, intratracheal,intralesional, percutaneous, endoscopical, transmucosal, sublingual andintestinal administration.

[0046] Pharmaceutically acceptable carriers for use in the compositionsof the present invention are well known to those of ordinary skill inthe art and are selected based upon a number of factors: the particularantitumor compound used, and its concentration, stability and intendedbioavailability; the disease, disorder or condition being treated withthe composition; the subject, its age, size and general condition; andthe route of administration. Suitable carriers are readily determined byone of ordinary skill in the art (see, for example, J. G. Nairn, in:Remington's Pharmaceutical Science (A. Gennaro, ed.), Mack PublishingCo., Easton, Pa., (1985), pp.1492-1517, the contents of which areincorporated herein by reference).

[0047] The compositions are preferably formulated as tablets,dispersible powders, pills, capsules, gelcaps, caplets, gels, liposomes,granules, solutions, suspensions, emulsions, syrups, elixirs, troches,dragees, lozenges, or any other dosage form which can be administeredorally. Techniques and compositions for making oral dosage forms usefulin the present invention are described in the following references: 7Modern Pharmaceutics, Chapters 9 and 10 (Banker & Rhodes, Editors,1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981);and Ansel, Introduction to Pharmaceutical Dosage Forms 2nd Edition(1976).

[0048] The compositions of the invention for oral administrationcomprise an effective antitumor amount of a compound of the invention ina pharmaceutically acceptable carrier. Suitable carriers for soliddosage forms include sugars, starches, and other conventional substancesincluding lactose, talc, sucrose, gelatin, carboxymethylcellulose, agar,mannitol, sorbitol, calcium phosphate, calcium carbonate, sodiumcarbonate, kaolin, alginic acid, acacia, corn starch, potato starch,sodium saccharin, magnesium carbonate, tragacanth, microcrystallinecellulose, colloidal silicon dioxide, croscarmellose sodium, talc,magnesium stearate, and stearic acid. Further, such solid dosage formsmay be uncoated or may be coated by known techniques; e.g., to delaydisintegration and absorption.

[0049] The antitumor compounds of the present invention are alsopreferably formulated for parenteral administration, e.g., formulatedfor injection via intravenous, intraarterial, subcutaneous, rectal,subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal,intraperitoneal, or intrasternal routes. The compositions of theinvention for parenteral administration comprise an effective antitumoramount of the antitumor compound in a pharmaceutically acceptablecarrier. Dosage forms suitable for parenteral administration includesolutions, suspensions, dispersions, emulsions or any other dosage formwhich can be administered parenterally. Techniques and compositions formaking parenteral dosage forms are known in the art.

[0050] Suitable carriers used in formulating liquid dosage forms fororal or parenteral administration include nonaqueous,pharmaceutically-acceptable polar solvents such as oils, alcohols,amides, esters, ethers, ketones, hydrocarbons and mixtures thereof, aswell as water, saline solutions, dextrose solutions (e.g., DW5),electrolyte solutions, or any other aqueous, pharmaceutically acceptableliquid.

[0051] Suitable nonaqueous, pharmaceutically-acceptable polar solventsinclude, but are not limited to, alcohols (e.g., α-glycerol formal,β-glycerol formal, 1, 3-butyleneglycol, aliphatic or aromatic alcoholshaving 2-30 carbon atoms such as methanol, ethanol, propanol,isopropanol, butanol, t-butanol, hexanol, octanol, amylene hydrate,benzyl alcohol, glycerin (glycerol), glycol, hexylene glycol,tetrahydrofurfuryl alcohol, lauryl alcohol, cetyl alcohol, or stearylalcohol, fatty acid esters of fatty alcohols such as polyalkyleneglycols (e.g., polypropylene glycol, polyethylene glycol), sorbitan,sucrose and cholesterol); amides (e.g., dimethylacetamide (DMA), benzylbenzoate DMA, dimethylformamide, N-(β-hydroxyethyl)-lactamide, N,N-dimethylacetamide_amides, 2-pyrrolidinone, 1-methyl-2-pyrrolidinone,or polyvinylpyrrolidone); esters (e.g., 1-methyl-2-pyrrolidinone,2-pyrrolidinone, acetate esters such as monoacetin, diacetin, andtriacetin, aliphatic or aromatic esters such as ethyl caprylate oroctanoate, alkyl oleate, benzyl benzoate, benzyl acetate,dimethylsulfoxide (DMSO), esters of glycerin such as mono, di, ortri-glyceryl citrates or tartrates, ethyl benzoate, ethyl acetate, ethylcarbonate, ethyl lactate, ethyl oleate, fatty acid esters of sorbitan,fatty acid derived PEG esters, glyceryl monostearate, glyceride esterssuch as mono, di, or tri-glycerides, fatty acid esters such as isopropylmyristrate, fatty acid derived PEG esters such as PEG-hydroxyoleate andPEG-hydroxystearate, N-methyl pyrrolidinone, pluronic 60,polyoxyethylene sorbitol oleic polyesters such as poly(ethoxylated)₃₀₋₆₀sorbitol poly(oleate)₂₋₄, poly(oxyethylene)₁₅₋₂₀ monooleate,poly(oxyethylene)₁₅₋₂₀ mono 12-hydroxystearate, andpoly(oxyethylene)₁₅₋₂₀ mono ricinoleate, polyoxyethylene sorbitan esterssuch as polyoxyethylene-sorbitan monooleate, polyoxyethylene-sorbitanmonopalmitate, polyoxyethylene-sorbitan monolaurate,polyoxyethylene-sorbitan monostearate, and Polysorbate® 20, 40, 60 or 80from ICI Americas, Wilmington, De., polyvinylpyrrolidone, alkyleneoxymodified fatty acid esters such as polyoxyl 40 hydrogenated castor oiland polyoxyethylated castor oils (e.g., Cremophor® EL solution orCremophor® RH 40 solution), saccharide fatty acid esters (i.e., thecondensation product of a monosaccharide (e.g., pentoses such as ribose,ribulose, arabinose, xylose, lyxose and xylulose, hexoses such asglucose, fructose, galactose, mannose and sorbose, trioses, tetroses,heptoses, and octoses), disaccharide (e.g., sucrose, maltose, lactoseand trehalose) or oligosaccharide or mixture thereof with a C₄- C₂₂fatty acid(s)(e.g., saturated fatty acids such as caprylic acid, capricacid, lauric acid, myristic acid, palmitic acid and stearic acid, andunsaturated fatty acids such as palmitoleic acid, oleic acid, elaidicacid, erucic acid and linoleic acid)), or steroidal esters); alkyl,aryl, or cyclic ethers having 2-30 carbon atoms (e.g., diethyl ether,tetrahydrofuran, dimethyl isosorbide, diethylene glycol monoethylether); glycofurol (tetrahydrofurfuryl alcohol polyethylene glycolether); ketones having 3-30 carbon atoms (e.g., acetone, methyl ethylketone, methyl isobutyl ketone); aliphatic, cycloaliphatic or aromatichydrocarbons having 4-30 carbon atoms (e.g., benzene, cyclohexane,dichloromethane, dioxolanes, hexane, n-decane, n-dodecane, n-hexane,sulfolane, tetramethylenesulfon, tetramethylenesulfoxide, toluene,dimethylsulfoxide (DMSO), or tetramethylenesulfoxide); oils of mineral,vegetable, animal, essential or synthetic origin (e.g., mineral oilssuch as aliphatic or wax-based hydrocarbons, aromatic hydrocarbons,mixed aliphatic and aromatic based hydrocarbons, and refined paraffinoil, vegetable oils such as linseed, tung, safflower, soybean, castor,cottonseed, groundnut, rapeseed, coconut, palm, olive, corn, corn germ,sesame, persic and peanut oil and glycerides such as mono-, di- ortriglycerides, animal oils such as fish, marine, sperm, cod-liver,haliver, squalene, squalane, and shark liver oil, oleic oils, andpolyoxyethylated castor oil); alkyl or aryl halides having 1-30 carbonatoms and optionally more than one halogen substituent; methylenechloride; monoethanolamine; petroleum benzin; trolamine; omega-3polyunsaturated fatty acids (e.g., alpha-linolenic acid,eicosapentaenoic acid, docosapentaenoic acid, or docosahexaenoic acid);polyglycol ester of 12-hydroxystearic acid and polyethylene glycol(Solutol® HS-15, from BASF, Ludwigshafen, Germany); polyoxyethyleneglycerol; sodium laurate; sodium oleate; or sorbitan monooleate.

[0052] Other pharmaceutically acceptable solvents for use in theinvention are well known to those of ordinary skill in the art, and areidentified in The Chemotherapy Source Book (Williams & WilkensPublishing), The Handbook of Pharmaceutical Excipients, (AmericanPharmaceutical Association, Washington, D.C., and The PharmaceuticalSociety of Great Britain, London, England, 1968), Modern Pharmaceutics,(G. Banker et al., eds., 3d ed.)(Marcel Dekker, Inc., New York, N.Y.,1995), The Pharmacological Basis of Therapeutics, (Goodman & Gilman,McGraw Hill Publishing), Pharmaceutical Dosage Forms, (H. Lieberman etal., eds., )(Marcel Dekker, Inc., New York, N.Y., 1980), Remington'sPharmaceutical Sciences (A. Gennaro, ed., 19th ed.)(Mack Publishing,Easton, Pa, 1995), The United States Pharmacopeia 24, The NationalFormulary 19, (National Publishing, Philadelphia, Pa., 2000), A. J.Spiegel et al., and Use of Nonaqueous Solvents in Parenteral Products,JOURNAL OF PHARMACEUTICAL SCIENCES, Vol. 52, No.10, pp. 917-927 (1963).

[0053] Preferred solvents include those known to stabilize the antitumorcompounds, such as oils rich in triglycerides, for example, saffloweroil, soybean oil or mixtures thereof, and alkyleneoxy modified fattyacid esters such as polyoxyl 40 hydrogenated castor oil andpolyoxyethylated castor oils (e.g., Cremophor® EL solution or Cremophor®RH 40 solution). Commercially available triglycerides includeIntralipid® emulsified soybean oil (Kabi-Pharmacia Inc., Stockholm,Sweden), Nutralipid ® emulsion (McGaw, Irvine, Calif.), Liposyn® II 20%emulsion (a 20% fat emulsion solution containing 100 mg safflower oil,100 mg soybean oil, 12 mg egg phosphatides, and 25 mg glycerin per ml ofsolution; Abbott Laboratories, Chicago, Ill.), Liposyn® III 2% emulsion(a 2% fat emulsion solution containing 100 mg safflower oil, 100 mgsoybean oil, 12 mg egg phosphatides, and 25 mg glycerin per ml ofsolution; Abbott Laboratories, Chicago, Ill.), natural or syntheticglycerol derivatives containing the docosahexaenoyl group at levelsbetween 25% and 100% by weight based on the total fatty acid content(Dhasco® (from Martek Biosciences Corp., Columbia, Md.), DHA Maguro®(from Daito Enterprises, Los Angeles, Calif.), Soyacal®, andTravemulsion®. Ethanol is a preferred solvent for use in dissolving theantitumor compound to form solutions, emulsions, and the like.

[0054] Additional minor components can be included in the compositionsof the invention for a variety of purposes well known in thepharmaceutical industry. These components will for the most part impartproperties which enhance retention of the antitumor compound at the siteof administration, protect the stability of the composition, control thepH, facilitate processing of the antitumor compound into pharmaceuticalformulations, and the like. Preferably, each of these components isindividually present in less than about 15 weight % of the totalcomposition, more preferably less than about 5 weight %, and mostpreferably less than about 0.5 weight % of the total composition. Somecomponents, such as fillers or diluents, can constitute up to 90 wt. %of the total composition, as is well known in the formulation art. Suchadditives include cryoprotective agents for preventing reprecipitationof the taxane, surface active, wetting or emulsifying agents (e.g.,lecithin, polysorbate-80, Tween® 80, pluronic 60, polyoxyethylenestearate ), preservatives (e.g., ethyl-p-hydroxybenzoate), microbialpreservatives (e.g., benzyl alcohol, phenol, m-cresol, chlorobutanol,sorbic acid, thimerosal and paraben), agents for adjusting pH orbuffering agents (e.g., acids, bases, sodium acetate, sorbitanmonolaurate), agents for adjusting osmolarity (e.g., glycerin),thickeners (e.g., aluminum monostearate, stearic acid, cetyl alcohol,stearyl alcohol, guar gum, methyl cellulose, hydroxypropylcellulose,tristearin, cetyl wax esters, polyethylene glycol), colorants, dyes,flow aids, non-volatile silicones (e.g., cyclomethicone), clays (e.g.,bentonites), adhesives, bulking agents, flavorings, sweeteners,adsorbents, fillers (e.g., sugars such as lactose, sucrose, mannitol, orsorbitol, cellulose, or calcium phosphate), diluents (e.g., water,saline, electrolyte solutions), binders (e.g., starches such as maizestarch, wheat starch, rice starch, or potato starch, gelatin, gumtragacanth, methyl cellulose, hydroxypropyl methylcellulose, sodiumcarboxymethyl cellulose, polyvinylpyrrolidone, sugars, polymers,acacia), disintegrating agents (e.g., starches such as maize starch,wheat starch, rice starch, potato starch, or carboxymethyl starch,cross-linked polyvinyl pyrrolidone, agar, alginic acid or a salt thereofsuch as sodium alginate, croscarmellose sodium or crospovidone),lubricants (e.g., silica, talc, stearic acid or salts thereof such asmagnesium stearate, or polyethylene glycol), coating agents (e.g.,concentrated sugar solutions including gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, or titanium dioxide),and antioxidants (e.g., sodium metabisulfite, sodium bisulfite, sodiumsulfite, dextrose, phenols, and thiophenols).

[0055] In a preferred embodiment, a pharmaceutical composition of theinvention comprises at least one nonaqueous, pharmaceutically acceptablesolvent and an antitumor compound having a solubility in ethanol of atleast about 100, 200, 300, 400, 500, 600, 700 or 800 mg/ml. While notbeing bound to a particular theory, it is believed that the ethanolsolubility of the antitumor compound may be directly related to itsefficacy. The antitumor compound can also be capable of beingcrystallized from a solution. In other words, a crystalline antitumorcompound, such as compound 1393, can be dissolved in a solvent to form asolution and then recrystallized upon evaporation of the solvent withoutthe formation of any amorphous antitumor compound. It is also preferredthat the antitumor compound have an ID50 value (i.e, the drugconcentration producing 50% inhibition of colony formation) of at least4, 5, 6, 7, 8, 9, or 10 times less that of paclitaxel when measuredaccording to the protocol set forth in the working examples.

[0056] Dosage form administration by these routes may be continuous orintermittent, depending, for example, upon the patient's physiologicalcondition, whether the purpose of the administration is therapeutic orprophylactic, and other factors known to and assessable by a skilledpractitioner.

[0057] Dosage and regimens for the administration of the pharmaceuticalcompositions of the invention can be readily determined by those withordinary skill in treating cancer. It is understood that the dosage ofthe antitumor compounds will be dependent upon the age, sex, health, andweight of the recipient, kind of concurrent treatment, if any, frequencyof treatment, and the nature of the effect desired. For any mode ofadministration, the actual amount of antitumor compound delivered, aswell as the dosing schedule necessary to achieve the advantageouseffects described herein, will also depend, in part, on such factors asthe bioavailability of the antitumor compound, the disorder beingtreated, the desired therapeutic dose, and other factors that will beapparent to those of skill in the art. The dose administered to ananimal, particularly a human, in the context of the present inventionshould be sufficient to effect the desired therapeutic response in theanimal over a reasonable period of time. Preferably, an effective amountof the antitumor compound, whether administered orally or by anotherroute, is any amount which would result in a desired therapeuticresponse when administered by that route. Preferably, the compositionsfor oral administration are prepared in such a way that a single dose inone or more oral preparations contains at least 20 mg of the antitumorcompound per m² of patient body surface area, or at least 50, 100, 150,200, 300, 400, or 500 mg of the antitumor compound per m²of patient bodysurface area, wherein the average body surface area for a human is 1.8m². Preferably, a single dose of a composition for oral administrationcontains from about 20 to about 600 mg of the antitumor compound perm²of patient body surface area, more preferably from about 25 to about400 mg/m² even more preferably, from about 40 to about 300 mg/m², andeven more preferably from about 50 to about 200 mg/m². Preferably, thecompositions for parenteral administration are prepared in such a waythat a single dose contains at least 20 mg of the antitumor compound perm²of patient body surface area, or at least 40, 50, 100, 150, 200, 300,400, or 500 mg of the antitumor compound per m² of patient body surfacearea. Preferably, a single dose in one or more parenteral preparationscontains from about 20 to about 500 mg of the antitumor compound perm²of patient body surface area, more preferably from about 40 to about400 mg/m² and even more preferably, from about 60 to about 350 mg/m².However, the dosage may vary depending on the dosing schedule which canbe adjusted as necessary to achieve the desired therapeutic effect. Itshould be noted that the ranges of effective doses provided herein arenot intended to limit the invention and represent preferred dose ranges.The most preferred dosage will be tailored to the individual subject, asis understood and determinable by one of ordinary skill in the artwithout undue experimentation.

[0058] The concentration of the antitumor compound in a liquidpharmaceutical composition is preferably between about 0.01 mg and about10 mg per ml of the composition, more preferably between about 0.1 mgand about 7 mg per ml, even more preferably between about 0.5 mg andabout 5 mg per ml, and most preferably between about 1.5 mg and about 4mg per ml. Relatively low concentrations are generally preferred becausethe antitumor compound is most soluble in the solution at lowconcentrations. The concentration of the antitumor compound in a solidpharmaceutical composition for oral administration is preferably betweenabout 5 weight % and about 50 weight %, based on the total weight of thecomposition, more preferably between about 8 weight % and about 40weight %, and most preferably between about 10 weight % and about 30weight %.

[0059] In one embodiment, solutions for oral administration are preparedby dissolving an antitumor compound in any pharmaceutically acceptablesolvent capable of dissolving the compound (e.g., ethanol or methylenechloride) to form a solution. An appropriate volume of a carrier whichis a solution, such as Cremophor® EL solution, is added to the solutionwhile stirring to form a pharmaceutically acceptable solution for oraladministration to a patient. If desired, such solutions can beformulated to contain a minimal amount of, or to be free of, ethanol,which is known in the art to cause adverse physiological effects whenadministered at certain concentrations in oral formulations.

[0060] In another embodiment, powders or tablets for oral administrationare prepared by dissolving an antitumor compound in any pharmaceuticallyacceptable solvent capable of dissolving the compound (e.g.,ethanol ormethylene chloride) to form a solution. The solvent can optionally becapable of evaporating when the solution is dried under vacuum. Anadditional carrier can be added to the solution prior to drying, such asCremophor® EL solution. The resulting solution is dried under vacuum toform a glass. The glass is then mixed with a binder to form a powder.The powder can be mixed with fillers or other conventional tablettingagents and processed to form a tablet for oral administration to apatient. The powder can also be added to any liquid carrier as describedabove to form a solution, emulsion, suspension or the like for oraladministration.

[0061] Emulsions for parenteral administration can be prepared bydissolving an antitumor compound in any pharmaceutically acceptablesolvent capable of dissolving the compound (e.g., ethanol or methylenechloride) to form a solution. An appropriate volume of a carrier whichis an emulsion, such as Liposyn® II or Liposyn® III emulsion, is addedto the solution while stirring to form a pharmaceutically acceptableemulsion for parenteral administration to a patient. If desired, suchemulsions can be formulated to contain a minimal amount of, or to befree of, ethanol or Cremophor® solution, which are known in the art tocause adverse physiological effects when administered at certainconcentrations in parenteral formulations.

[0062] Solutions for parenteral administration can be prepared bydissolving an antitumor compound in any pharmaceutically acceptablesolvent capable of dissolving the compound (e.g., ethanol or methylenechloride) to form a solution. An appropriate volume of a carrier whichis a solution, such as Cremophor® solution, is added to the solutionwhile stirring to form a pharmaceutically acceptable solution forparenteral administration to a patient. If desired, such solutions canbe formulated to contain a minimal amount of, or to be free of, ethanolor Cremophor® solution, which are known in the art to cause adversephysiological effects when administered at certain concentrations inparenteral formulations.

[0063] If desired, the emulsions or solutions described above for oralor parenteral administration can be packaged in IV bags, vials or otherconventional containers in concentrated form and diluted with anypharmaceutically acceptable liquid, such as saline, to form anacceptable taxane concentration prior to use as is known in the art.

[0064] Definitions

[0065] The terms “hydrocarbon” and “hydrocarbyl” as used herein describeorganic compounds or radicals consisting exclusively of the elementscarbon and hydrogen. These moieties include alkyl, alkenyl, alkynyl, andaryl moieties. These moieties also include alkyl, alkenyl, alkynyl, andaryl moieties substituted with other aliphatic or cyclic hydrocarbongroups, such as alkaryl, alkenaryl and alkynaryl. Unless otherwiseindicated, these moieties preferably comprise 1 to 20 carbon atoms.

[0066] The “substituted hydrocarbyl” moieties described herein arehydrocarbyl moieties which are substituted with at least one atom otherthan carbon, including moieties in which a carbon chain atom issubstituted with a hetero atom such as nitrogen, oxygen, silicon,phosphorous, boron, sulfur, or a halogen atom. These substituentsinclude halogen, heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy,hydroxy, protected hydroxy, keto, acyl, acyloxy, nitro, amino, amido,nitro, cyano, thiol, ketals, acetals, esters and ethers.

[0067] The term “heteroatom” shall mean atoms other than carbon andhydrogen.

[0068] The “heterosubstituted methyl” moieties described herein aremethyl groups in which the carbon atom is covalently bonded to at leastone heteroatom and optionally with hydrogen, the heteroatom being, forexample, a nitrogen, oxygen, silicon, phosphorous, boron, sulfur, orhalogen atom. The heteroatom may, in turn, be substituted with otheratoms to form a heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy,hydroxy, protected hydroxy, oxy, acyloxy, nitro, amino, amido, thiol,ketals, acetals, esters or ether moiety.

[0069] The “heterosubstituted acetate” moieties described herein areacetate groups in which the carbon of the methyl group is covalentlybonded to at least one heteroatom and optionally with hydrogen, theheteroatom being, for example, a nitrogen, oxygen, silicon, phosphorous,boron, sulfur, or halogen atom. The heteroatom may, in turn, besubstituted with other atoms to form a heterocyclo, alkoxy, alkenoxy,alkynoxy, aryloxy, hydroxy, protected hydroxy, oxy, acyloxy, nitro,amino, amido, thiol, ketals, acetals, esters or ether moiety.

[0070] Unless otherwise indicated, the alkyl groups described herein arepreferably lower alkyl containing from one to eight carbon atoms in theprincipal chain and up to 20 carbon atoms. They may be straight orbranched chain or cyclic and include methyl, ethyl, propyl, isopropyl,butyl, hexyl and the like.

[0071] Unless otherwise indicated, the alkenyl groups described hereinare preferably lower alkenyl containing from two to eight carbon atomsin the principal chain and up to 20 carbon atoms. They may be straightor branched chain or cyclic and include ethenyl, propenyl, isopropenyl,butenyl, isobutenyl, hexenyl, and the like.

[0072] Unless otherwise indicated, the alkynyl groups described hereinare preferably lower alkynyl containing from two to eight carbon atomsin the principal chain and up to 20 carbon atoms. They may be straightor branched chain and include ethynyl, propynyl, butynyl, isobutynyl,hexynyl, and the like.

[0073] The terms “aryl” or “ar” as used herein alone or as part ofanother group denote optionally substituted homocyclic aromatic groups,preferably monocyclic or bicyclic groups containing from 6 to 12 carbonsin the ring portion, such as phenyl, biphenyl, naphthyl, substitutedphenyl, substituted biphenyl or substituted naphthyl. Phenyl andsubstituted phenyl are the more preferred aryl.

[0074] The terms “halogen” or “halo” as used herein alone or as part ofanother group refer to chlorine, bromine, fluorine, and iodine.

[0075] The terms “heterocyclo” or “heterocyclic” as used herein alone oras part of another group denote optionally substituted, fully saturatedor unsaturated, monocyclic or bicyclic, aromatic or nonaromatic groupshaving at least one heteroatom in at least one ring, and preferably 5 or6 atoms in each ring. The heterocyclo group preferably has 1 or 2 oxygenatoms, 1 or 2 sulfur atoms, and/or 1 to 4 nitrogen atoms in the ring,and may be bonded to the remainder of the molecule through a carbon orheteroatom. Exemplary heterocyclo include heteroaromatics such as furyl,thienyl, pyridyl, oxazolyl, pyrrolyl, indolyl, quinolinyl, orisoquinolinyl and the like. Exemplary substituents include one or moreof the following groups: hydrocarbyl, substituted hydrocarbyl, keto,hydroxy, protected hydroxy, acyl, acyloxy, alkoxy, alkenoxy, alkynoxy,aryloxy, halogen, amido, amino, nitro, cyano, thiol, ketals, acetals,esters and ethers.

[0076] The term “heteroaromatic” as used herein alone or as part ofanother group denote optionally substituted aromatic groups having atleast one heteroatom in at least one ring, and preferably 5 or 6 atomsin each ring. The heteroaromatic group preferably has 1 or 2 oxygenatoms, 1 or 2 sulfur atoms, and/or 1 to 4 nitrogen atoms in the ring,and may be bonded to the remainder of the molecule through a carbon orheteroatom. Exemplary heteroaromatics include furyl, thienyl, pyridyl,oxazolyl, pyrrolyl, indolyl, quinolinyl, or isoquinolinyl and the like.Exemplary substituents include one or more of the following groups:hydrocarbyl, substituted hydrocarbyl, keto, hydroxy, protected hydroxy,acyl, acyloxy, alkoxy, alkenoxy, alkynoxy, aryloxy, halogen, amido,amino, nitro, cyano, thiol, ketals, acetals, esters and ethers.

[0077] The term “acyl,” as used herein alone or as part of anothergroup, denotes the moiety formed by removal of the hydroxyl group fromthe group —COOH of an organic carboxylic acid, e.g., RC(O)—, wherein Ris R¹, R¹O—, R¹R²N—, or R¹S—, R¹ is hydrocarbyl, heterosubstitutedhydrocarbyl, or heterocyclo and R² is hydrogen, hydrocarbyl orsubstituted hydrocarbyl.

[0078] The term “acyloxy,” as used herein alone or as part of anothergroup, denotes an acyl group as described above bonded through an oxygenlinkage (—O—), e.g., RC(O)O— wherein R is as defined in connection withthe term “acyl.”

[0079] Unless otherwise indicated, the alkoxycarbonyloxy moietiesdescribed herein comprise lower hydrocarbon or substituted hydrocarbonor substituted hydrocarbon moieties.

[0080] Unless otherwise indicated, the carbamoyloxy moieties describedherein are derivatives of carbamic acid in which one or both of theamine hydrogens is optionally replaced by a hydrocarbyl, substitutedhydrocarbyl or heterocyclo moiety.

[0081] The terms “hydroxyl protecting group” and “hydroxy protectinggroup” as used herein denote a group capable of protecting a freehydroxyl group (“protected hydroxyl”) which, subsequent to the reactionfor which protection is employed, may be removed without disturbing theremainder of the molecule. A variety of protecting groups for thehydroxyl group and the synthesis thereof may be found in “ProtectiveGroups in Organic Synthesis” by T. W. Greene, John Wiley and Sons, 1981,or Fieser & Fieser. Exemplary hydroxyl protecting groups includemethoxymethyl, 1-ethoxyethyl, benzyloxymethyl,(.beta.-trimethylsilylethoxy)methyl, tetrahydropyranyl,2,2,2-trichloroethoxycarbonyl, t-butyl(diphenyl)silyl, trialkylsilyl,trichloromethoxycarbonyl and 2,2,2-trichloroethoxymethyl.

[0082] As used herein, “Ac” means acetyl; “Bz” means benzoyl; “Et” meansethyl; “Me” means methyl; “Ph” means phenyl; “iPr” means isopropyl;“tBu” and “t-Bu” means tert-butyl; “R” means lower alkyl unlessotherwise defined; “py” means pyridine or pyridyl; “TES” meanstriethylsilyl; “TMS” means trimethylsilyl; “LAH” means lithium aluminumhydride; “10-DAB” means 10-desacetylbaccatin III”; “amine protectinggroup” includes, but is not limited to, carbamates, for example,2,2,2-trichloroethylcarbamate or tertbutylcarbamate; “protected hydroxy”means—OP wherein P is a hydroxy protecting group; “tBuOCO” meanstert-butoxycarbonyl; “tAmOCO” means tert-amyloxycarbonyl; “PhCO meansphenylcarbonyl”; “2-FuCO” means 2-furylcarbonyl; “2-ThCO” means2-thienylcarbonyl; “2-PyCO” means 2-pyridylcarbonyl; “3-PyCO” means3-pyridylcarbonyl; “4-PyCO” means 4-pyridylcarbonyl; “C₄H₇CO” meansbutenylcarbonyl; “EtOCO” means ethoxycarbonyl; “ibueCO” meansisobutenylcarbonyl; “iBuCO” means isobutylcarbonyl; “iBuOCO” meansisobutoxycarbonyl; “iPrOCO” means isopropyloxycarbonyl; “nPrOCO” meansn-propyloxycarbonyl; “nPrCO” means n-propylcarbonyl; “tC₃H₅CO” meanstrans-propenyl carbonyl;“ibue” means isobutenyl; “THF” meanstetrahydrofuran; “DMAP” means 4-dimethylamino pyridine; and “LHMDS”means lithium hexamethyl disilazanide.

[0083] The following examples illustrate the invention.

Example 1

[0084]N-Debenzoyl-N-tert-amyloxycarbonyl-3′-desphenyl-3′-(2-furyl)-10-methoxyacetyltaxol (6515)

[0085] To a solution ofN-debenzoyl-N-tert-amyloxycarbonyl-3′-desphenyl-3′-(2-furyl)-2′-(2-methoxy-2-propyl)-7-benzyloxycarbonyl-10-deacetyl-10-trimethylsilyltaxol (3.50 g) in 40 mL of 1:1 acetonitrile-pyridine at 0° C. (ice-waterbath) was added dropwise over 10 minutes, 10 mL of 48% aqueoushydrofluoric acid. The cooling bath was then removed and the reactionstirred at ambient temperature for 8 h, diluted with 200 mL of ethylacetate and washed with 25 mL of water, 2×20 mL of saturated aqueousNaHCO₃ and 25 mL of saturated aqueous NaCl. The organic layer was thendried over sodium sulfate and concentrated under reduced pressure togiveN-debenzoyl-N-tert-amyloxycarbonyl-3′-desphenyl-3′-(2-furyl)-7-benzyloxycarbonyl-10-deacetyltaxol as a white solid which was dried under high vacuum (0.1 mmHg, 12h) and used directly in the next step.

[0086] To a solution ofN-debenzoyl-N-tert-amyloxycarbonyl-3′-desphenyl-3′-(2-furyl)-7-benzyloxycarbonyl-10-deacetyltaxol (2.17 g, 2.293 mmol) in anhydrous methylene chloride (6 mL) wasadded with stirring triethylamine (1.60 mL, 11.46 mmol) followed by thedropwise addition of 0.46 mL of triethylsilyl chloride. TLC of themixture (silica gel, 2:3 ethyl acetate:hexane) after 2 h, showed theformation of only one product. Saturated aqueous NaHCO₃, 2 mL was addedto the reaction which was then diluted with 70 mL of ethyl acetate,washed with 10 mL of saturated aqueous NaHCO₃ and 15 mL of saturatedaqueous NaCl. The organic layer was dried over sodium sulfate andconcentrated under reduced pressure to give pureN-debenzoyl-N-tert-amyloxycarbonyl-3′-desphenyl-3′-(2-furyl)-2′-triethylsilyl-7-benzyloxycarbonyl-10-deacetyltaxol as a white solid (2.21 g, 91%)

[0087] To a solution ofN-debenzoyl-N-tert-amyloxycarbonyl-3′-desphenyl-3′-(2-furyl)-2′-triethylsilyl-7-benzyloxycarbonyl-10-deacetyltaxol (660 mg, 0.622 mmol) in 4 mL anhydrous pyridine at 0° C. was addedDMAP (20 mg, 0.16 mmol) under a nitrogen atmosphere. To this mixture wasadded drop wise methoxyacetyl chloride (220 mL, 2.489 mmol). TLC (silicagel, 2:3 ethyl acetate:hexane) after 2 h showed no starting material.The reaction was cooled to 0° C. (ice-water bath) and quenched by adding80 mL of water.

[0088] To the reaction at 0° C. (ice-water bath) was added 4 mL ofacetonitrile and 2 mL of 48% aqueous hydrofluoric acid and the coolingbath was removed. The reaction was stirred at room temperature for 8.0h, diluted with 60 mL of ethyl acetate and washed with 10 mL ofsaturated aqueous NaHCO₃ and 15 mL of saturated aqueous NaCl. Theorganic layer was dried over Na₂SO₄ and concentrated under reducepressure to give 602 mg of a yellow solid which was purified byflash-chromatography (silica gel, 1:1 ethyl acetate:hexane) to give 538mg (85%) of pureN-debenzoyl-N-tert-amyloxycarbonyl-3′-desphenyl-3′-(2-furyl)-7-benzyloxycarbonyl-10-deacetyl-10-methoxyacetyltaxol (TL-650): mp 145-146° C.; Anal. Calcd. for C₅₃H₆₃NO₁₉: C, 62.53;H, 6.24. Found: C, 62.26; H, 6.20.

[0089] To a solution ofN-debenzoyl-N-tert-amyloxycarbonyl-3′-desphenyl-3′-(2-furyl)-7-benzyloxycarbonyl-10-deacetyl-10-methoxyacetyltaxol (TL-650, 350 mg, 0.343 mmol) in 15 mL ethyl acetate was added 10%Pd-C (100 mg). The mixture was stirred under a H₂ atmosphere (usinglatex balloons) for 1 h, when TLC (silica gel, 1:1 ethyl acetate:hexane)showed no starting material. The reaction was then filtered throughcelite (3 g) and the celite pad washed with 25 mL of ethyl acetate. Thecombined organic extract was concentrated under reduced pressure to give315 mg of a white solid which was purified by flash-chromatography(silica gel, 55:45 ethyl acetate:hexane) to give 283 mg (93%) of pureN-debenzoyl-N-tert-amyloxycarbonyl-3′-desphenyl-3′-(2-furyl)--10-deacetyl-10-methoxyacetyl taxol: mp 164-166° C.; ¹H NMR (CDCl₃) 8.13(m, 2H), 7.62(m, 1H), 7.46-7.51(m, 2H), 7.41 (m, 1H), 6.41 (bs, 1H),6.39(dd, J=3.1, 1.5 Hz, 1H), 6.25 (d, J=3.1 Hz, 1H), 6.22(dd, J=8.8, 8.7Hz, 1H), 5.67(1H), 5.22-5.38(m, 2H), 4.98(m, 1H), 4.76(m, 1H), 4.42(m,2H), 4.36 (d, J=9.3 Hz, 1H), 4.28(m, 1H), 4.21 (d, J=9.3 Hz, 1H), 3.82(m, 1H), 3.42 (s, 3H), 3.41 (d, J=5.5 Hz, 1H), 2.55-2.60(m, 1H), 2.41(s, 3H), 2.20-2.38(m, 2H), 1.92 (s, 3H), 1.91-1.94 (m, 1H), 1.68 (bs,3H), 1.62-1.68(m, 2H), 1.62(S, 3H), 1.36(s, 3H), 1.34(s, 3H), 1.23(s,3H), 1.16(s, 3H), 0.80(t, J=8.2 Hz, 3H); Anal. Calcd. for C₄₅H₅₇NO₁₇.½H₂O: C, 60.47; H, 6.49. Found: C, 60.64; H, 6.45.

Example 2

[0090] The procedures described in Example 1 were repeated, but othersuitably protected β-lactams were substituted for the β-lactam ofExample 1 to prepare the series of compounds having structural formula(13) and the combinations of substituents identified in the followingtable

(13) Compound X₅ X₃ R₁₀ 6577 tAmOCO 2-furyl AcOAcO— 6515 tAmOCO 2-furylMeOAcO— 6066 tC₃H₅CO 2-furyl MeOAcO— 6111 tC₃H₅CO 2-furyl PhOAcO—

Example 3

[0091] Following the processes described in Example 1 and elsewhereherein, the following specific taxanes having structural formula 14 maybe prepared, wherein R₁₀ is R_(10a)COO— and R_(10a) is heterosubstitutedmethyl. In one embodiment, R_(10a) is chloromethyl, hydroxymethyl,methoxymethyl, ethoxymethyl, phenoxymethyl, acetoxymethyl,acyloxymethyl, or methylthiomethyl.

(14) X₅ X₃ R₁₀ tBuOCO— 2-furyl R_(10a)COO— tBuOCO— 3-furyl R_(10a)COO—tBuOCO— 2-thienyl R_(10a)COO— tBuOCO— 3-thienyl R_(10a)COO— tBuOCO—2-pyridyl R_(10a)COO— tBuOCO— 3-pyridyl R_(10a)COO— tBuOCO— 4-pyridylR_(10a)COO— tBuOCO— isobutenyl R_(10a)COO— tBuOCO— isopropyl R_(10a)COO—tBuOCO— cyclopropyl R_(10a)COO— tBuOCO— cyclobutyl R_(10a)COO— tBuOCO—cyclopentyl R_(10a)COO— tBuOCO— phenyl R_(10a)COO— benzoyl 2-furylR_(10a)COO— benzoyl 3-furyl R_(10a)COO— benzoyl 2-thienyl R_(10a)COO—benzoyl 3-thienyl R_(10a)COO— benzoyl 2-pyridyl R_(10a)COO— benzoyl3-pyridyl R_(10a)COO— benzoyl 4-pyridyl R_(10a)COO— benzoyl isobutenylR_(10a)COO— benzoyl isopropyl R_(10a)COO— benzoyl cyclopropylR_(10a)COO— benzoyl cyclobutyl R_(10a)COO— benzoyl cyclopentylR_(10a)COO— benzoyl phenyl R_(10a)COO— 2-FuCO— 2-furyl R_(10a)COO—2-FuCO— 3-furyl R_(10a)COO— 2-FuCO— 2-thienyl R_(10a)COO— 2-FuCO—3-thienyl R_(10a)COO— 2-FuCO— 2-pyridyl R_(10a)COO— 2-FuCO— 3-pyridylR_(10a)COO— 2-FuCO— 4-pyridyl R_(10a)COO— 2-FuCO— isobutenyl R_(10a)COO—2-FuCO— isopropyl R_(10a)COO— 2-FuCO— cyclopropyl R_(10a)COO— 2-FuCO—cyclobutyl R_(10a)COO— 2-FuCO— cyclopentyl R_(10a)COO— 2-FuCO— phenylR_(10a)COO— 2-ThCO— 2-furyl R_(10a)COO— 2-ThCO— 3-furyl R_(10a)COO—2-ThCO— cyclobutyl R_(10a)COO— 2-ThCO— cyclopentyl R_(10a)COO— 2-ThCO—phenyl R_(10a)COO— 2-PyCO— 2-furyl R_(10a)COO— 2-PyCO— 3-furylR_(10a)COO— 2-PyCO— 2-thienyl R_(10a)COO— 2-PyCO— 3-thienyl R_(10a)COO—2-PyCO— 2-pyridyl R_(10a)COO— 2-PyCO— 3-pyridyl R_(10a)COO— 2-PyCO—4-pyridyl R_(10a)COO— 2-PyCO— isobutenyl R_(10a)COO— 2-PyCO— isopropylR_(10a)COO— 2-PyCO— cyclopropyl R_(10a)COO— 2-PyCO— cyclobutylR_(10a)COO— 2-PyCO— cyclopentyl R_(10a)COO— 2-PyCO— phenyl R_(10a)COO—3-PyCO— 2-furyl R_(10a)COO— 3-PyCO— 3-furyl R_(10a)COO— 3-PyCO—2-thienyl R_(10a)COO— 3-PyCO— 3-thienyl R_(10a)COO— 3-PyCO— 2-pyridylR_(10a)COO— 3-PyCO— 3-pyridyl R_(10a)COO— 3-PyCO— 4-pyridyl R_(10a)COO—3-PyCO— isobutenyl R_(10a)COO— 3-PyCO— isopropyl R_(10a)COO— 3-PyCO—cyclopropyl R_(10a)COO— 3-PyCO— cyclobutyl R_(10a)COO— 3-PyCO—cyclopentyl R_(10a)COO— 3-PyCO— phenyl R_(10a)COO— 4-PyCO— 2-furylR_(10a)COO— 4-PyCO— 3-furyl R_(10a)COO— 4-PyCO— 2-thienyl R_(10a)COO—4-PyCO— 3-thienyl R_(10a)COO— 4-PyCO— 2-pyridyl R_(10a)COO— 4-PyCO—3-pyridyl R_(10a)COO— 4-PyCO— 4-pyridyl R_(10a)COO— 4-PyCO— isobutenylR_(10a)COO— 4-PyCO— isopropyl R_(10a)COO— 4-PyCO— cyclopropylR_(10a)COO— 4-PyCO— cyclobutyl R_(10a)COO— 4-PyCO— cyclopentylR_(10a)COO— 4-PyCO— phenyl R_(10a)COO— C₄H₇CO— 2-furyl R_(10a)COO—C₄H₇CO— 3-furyl R_(10a)COO— C₄H₇CO— 2-thienyl R_(10a)COO— C₄H₇CO—3-thienyl R_(10a)COO— C₄H₇CO— 2-pyridyl R_(10a)COO— C₄H₇CO— 3-pyridylR_(10a)COO— C₄H₇CO— 4-pyridyl R_(10a)COO— C₄H₇CO— isobutenyl R_(10a)COO—C₄H₇CO— isopropyl R_(10a)COO— C₄H₇CO— cyclopropyl R_(10a)COO— C₄H₇CO—cyclobutyl R_(10a)COO— C₄H₇CO— cyclopentyl R_(10a)COO— C₄H₇CO— phenylR_(10a)COO— EtOCO— 2-furyl R_(10a)COO— EtOCO— 3-furyl R_(10a)COO— EtOCO—2-thienyl R_(10a)COO— EtOCO— 3-thienyl R_(10a)COO— EtOCO— 2-pyridylR_(10a)COO— EtOCO— 3-pyridyl R_(10a)COO— EtOCO— 4-pyridyl R_(10a)COO—EtOCO— isobutenyl R_(10a)COO— EtOCO— isopropyl R_(10a)COO— EtOCO—cyclopropyl R_(10a)COO— EtOCO— cyclobutyl R_(10a)COO— EtOCO— cyclopentylR_(10a)COO— EtOCO— phenyl R_(10a)COO— ibueCO— 2-furyl R_(10a)COO—ibueCO— 3-furyl R_(10a)COO— ibueCO— 2-thienyl R_(10a)COO— ibueCO—3-thienyl R_(10a)COO— ibueCO— 2-pyridyl R_(10a)COO— ibueCO— 3-pyridylR_(10a)COO— ibueCO— 4-pyridyl R_(10a)COO— ibueCO— isobutenyl R_(10a)COO—ibueCO— isopropyl R_(10a)COO— ibueCO— cyclopropyl R_(10a)COO— ibueCO—cyclopropyl R_(10a)COO— ibueCO— cyclopentyl R_(10a)COO— ibueCO— phenylR_(10a)COO— iBuCO— 2-furyl R_(10a)COO— iBuCO— 3-furyl R_(10a)COO— iBuCO—2-thienyl R_(10a)COO— iBuCO— 3-thienyl R_(10a)COO— iBuCO— 2-pyridylR_(10a)COO— iBuCO— 3-pyridyl R_(10a)COO— iBuCO— 4-pyridyl R_(10a)COO—iBuCO— isobutenyl R_(10a)COO— iBuCO— isopropyl R_(10a)COO— iBuCO—cyclopropyl R_(10a)COO— iBuCO— cyclobutyl R_(10a)COO— iBuCO— cyclopentylR_(10a)COO— iBuCO— phenyl R_(10a)COO— iBuOCO— 2-furyl R_(10a)COO—iBuOCO— 3-furyl R_(10a)COO— iBuOCO— 2-thienyl R_(10a)COO— iBuOCO—3-thienyl R_(10a)COO— iBuOCO— 2-pyridyl R_(10a)COO— iBuOCO— 3-pyridylR_(10a)COO— iBuOCO— 4-pyridyl R_(10a)COO— iBuOCO— isobutenyl R_(10a)COO—iBuOCO— isopropyl R_(10a)COO— iBuOCO— cyclopropyl R_(10a)COO— iBuOCO—cyclobutyl R_(10a)COO— iBuOCO— cyclopentyl R_(10a)COO— iBuOCO— phenylR_(10a)COO— iPrOCO— 2-furyl R_(10a)COO— iPrOCO— 3-furyl R_(10a)COO—iPrOCO— 2-thienyl R_(10a)COO— iPrOCO— 3-thienyl R_(10a)COO— iPrOCO—2-pyridyl R_(10a)COO— iPrOCO— 3-pyridyl R_(10a)COO— iPrOCO— 4-pyridylR_(10a)COO— iPrOCO— isobutenyl R_(10a)COO— iPrOCO— isopropyl R_(10a)COO—iPrOCO— cyclopropyl R_(10a)COO— iPrOCO— cyclobutyl R_(10a)COO— iPrOCO—cyclopentyl R_(10a)COO— iPrOCO— phenyl R_(10a)COO— nPrOCO— 2-furylR_(10a)COO— nPrOCO— 3-furyl R_(10a)COO— nPrOCO— 2-thienyl R_(10a)COO—nPrOCO— 3-thienyl R_(10a)COO— nPrOCO— 2-pyridyl R_(10a)COO— nPrOCO—3-pyridyl R_(10a)COO— nPrOCO— 4-pyridyl R_(10a)COO— nPrOCO— isobutenylR_(10a)COO— nPrOCO— isopropyl R_(10a)COO— nPrOCO— cyclopropylR_(10a)COO— nPrOCO— cyclobutyl R_(10a)COO— nPrOCO— cyclopentylR_(10a)COO— nPrOCO— phenyl R_(10a)COO— nPrCO— 2-furyl R_(10a)COO— nPrCO—3-furyl R_(10a)COO— nPrCO— 2-thienyl R_(10a)COO— nPrCO— 3-thienylR_(10a)COO— nPrCO— 2-pyridyl R_(10a)COO— nPrCO— 3-pyridyl R_(10a)COO—nPrCO— 4-pyridyl R_(10a)COO— nPrCO— isobutenyl R_(10a)COO— nPrCO—isopropyl R_(10a)COO— nPrCO— cyclopropyl R_(10a)COO— nPrCO— cyclobutylR_(10a)COO— nPrCO— cyclopentyl R_(10a)COO— nPrCO— phenyl R_(10a)COO—

Example 4

[0092] Following the processes described in Example 1 and elsewhereherein, the following specific taxanes having structural formula 15 maybe prepared, wherein R₇ is hydroxy and R₁₀ in each of the series (thatis, each of series “A” through “K”) is as previously defined, includingwherein R₁₀ is R_(10a)COO— wherein R_(10a) is a heterosubstituted methylmoiety lacking a carbon atom which is in the beta position relative tothe carbon atom of which R_(10a) is a substituent. The heterosubstitutedmethyl is covalently bonded to at least one heteroatom and optionallywith hydrogen, the heteroatom being, for example, a nitrogen, oxygen,silicon, phosphorous, boron, sulfur, or halogen atom. The heteroatommay, in turn, be substituted with other atoms to form a heterocyclo,alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protected hydroxy, oxy,acyloxy, nitro, amino, amido, thiol, ketals, acetals, esters or ethermoiety. Exemplary R₁₀ substituents include R_(10a)COO— wherein R_(10a)is chloromethyl, hydroxymethyl, methoxymethyl, ethoxymethyl,phenoxymethyl, acetoxymethyl, acyloxymethyl, or methylthiomethyl.

[0093] In the “A” series of compounds, X₁₀ is as otherwise as definedherein. Preferably, heterocyclo is substituted or unsubstitued furyl,thienyl, or pyridyl, X₁₀ is substituted or unsubstitued furyl, thienyl,pyridyl, phenyl, or lower alkyl (e.g., tert-butyl), and R₇ and R₁₀ eachhave the beta stereochemical configuration.

[0094] In the “B” series of compounds, X₁₀ and R_(2a) are as otherwiseas defined herein. Preferably, heterocyclo is preferably substituted orunsubstitued furyl, thienyl, or pyridyl, X₁₀ is preferably substitutedor unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g.,tert-butyl), R_(2a) is preferably substituted or unsubstitued furyl,thienyl, pyridyl, phenyl, or lower alkyl, and R₇ and R₁₀ each have thebeta stereochemical configuration.

[0095] In the “C” series of compounds, X₁₀ and R_(9a) are as otherwiseas defined herein. Preferably, heterocyclo is preferably substituted orunsubstitued furyl, thienyl, or pyridyl, X₁₀ is preferably substitutedor unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g.,tert-butyl), R_(9a) is preferably substituted or unsubstitued furyl,thienyl, pyridyl, phenyl, or lower alkyl, and R₇, R₉ and R₁₀ each havethe beta stereochemical configuration.

[0096] In the “D” and “E” series of compounds, X₁₀ is as otherwise asdefined herein. Preferably, heterocyclo is preferably substituted orunsubstitued furyl, thienyl, or pyridyl, X₁₀ is preferably substitutedor unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g.,tert-butyl), and R₇, R₉ (series D only) and R₁₀ each have the betastereochemical configuration.

[0097] In the “F” series of compounds, X₁₀, R_(2a) and R_(9a) are asotherwise as defined herein. Preferably, heterocyclo is preferablysubstituted or unsubstitued furyl, thienyl, or pyridyl, X₁₀ ispreferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl,or lower alkyl (e.g., tert-butyl), R_(2a) is preferably substituted orunsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R₇, R₉and R₁₀ each have the beta stereochemical configuration.

[0098] In the “G” series of compounds, X₁₀ and R_(2a) are as otherwiseas defined herein. Preferably, heterocyclo is preferably substituted orunsubstitued furyl, thienyl, or pyridyl, X₁₀ is preferably substitutedor unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g.,tert-butyl), R_(2a) is preferably substituted or unsubstitued furyl,thienyl, pyridyl, phenyl, or lower alkyl, and R₇, R₉ and R₁₀ each havethe beta stereochemical configuration.

[0099] In the “H” series of compounds, X₁₀ is as otherwise as definedherein. Preferably, heterocyclo is preferably substituted orunsubstitued furyl, thienyl, or pyridyl, X₁₀ is preferably substitutedor unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g.,tert-butyl), R_(2a) is preferably substituted or unsubstitued furyl,thienyl, pyridyl, phenyl, or lower alkyl, and R₇ and R₁₀ each have thebeta stereochemical configuration.

[0100] In the “I” series of compounds, X₁₀ and R_(2a) are as otherwiseas defined herein. Preferably, heterocyclo is preferably substituted orunsubstitued furyl, thienyl, or pyridyl, X₁₀ is preferably substitutedor unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g.,tert-butyl), R_(2a) is preferably substituted or unsubstitued furyl,thienyl, pyridyl, phenyl, or lower alkyl, and R₇ and R₁₀ each have thebeta stereochemical configuration.

[0101] In the “J” series of compounds, X₁₀ and R_(2a) are as otherwiseas defined herein. Preferably, heterocyclo is preferably substituted orunsubstitued furyl, thienyl, or pyridyl, X₁₀ is preferably substitutedor unsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl (e.g.,tert-butyl), R_(2a) is preferably substituted or unsubstitued furyl,thienyl, pyridyl, phenyl, or lower alkyl, and R₇, R₉ and R₁₀ each havethe beta stereochemical configuration.

[0102] In the “K” series of compounds, X₁₀, R_(2a) and R_(9a) are asotherwise as defined herein. Preferably, heterocyclo is preferablysubstituted or unsubstitued furyl, thienyl, or pyridyl, X₁₀ ispreferably substituted or unsubstitued furyl, thienyl, pyridyl, phenyl,or lower alkyl (e.g., tert-butyl), R_(2a) is preferably substituted orunsubstitued furyl, thienyl, pyridyl, phenyl, or lower alkyl, and R₇, R₉and R₁₀ each have the beta stereochemical configuration.

[0103] Any substituents of each X₃, X₅, R₂, R₇, and R₉ may behydrocarbyl or any of the heteroatom containing substituents selectedfrom the group consisting of heterocyclo, alkoxy, alkenoxy, alkynoxy,aryloxy, hydroxy, protected hydroxy, keto, acyloxy, nitro, amino, amido,thiol, ketal, acetal, ester and ether moieties, but not phosphorouscontaining moieties.

(15) Series X₅ X₃ R₁₀ R₂ R₉ R₁₄ A1 —COOX₁₀ heterocyclo R_(10a)COO—C₆H₅COO— O H A2 —COX₁₀ heterocyclo R_(10a)COO— C₆H₅COO— O H A3 —CONHX₁₀heterocyclo R_(10a)COO— C₆H₅COO— O H A4 —COOX₁₀ optionally R_(10a)COO—C₆H₅COO— O H substituted C₂ to C₈ alkyl A5 —COX₁₀ optionally R_(10a)COO—C₆H₅COO— O H substituted C₂ to C₈ alkyl A6 —CONHX₁₀ optionallyR_(10a)COO— C₆H₅COO— O H substituted C₂ to C₈ alkyl A7 —COOX₁₀optionally R_(10a)COO— C₆H₅COO— O H substituted C₂ to C₈ alkenyl A8—COX₁₀ optionally R_(10a)COO— C₆H₅COO— O H substituted C₂ to C₈ alkenylA9 —CONHX₁₀ optionally R_(10a)COO— C₆H₅COO— O H substituted C₂ to C₈alkenyl A10 —COOX₁₀ optionally R_(10a)COO— C₆H₅COO— O H substituted C₂to C₈ alkynyl A11 —COX₁₀ optionally R_(10a)COO— C₆H₅COO— O H substituedC₂ to C₈ alkynyl A12 —CONHX₁₀ optionally R_(10a)COO— C₆H₅COO— O Hsubstituted C₂ to C₈ alkynyl B1 —COOX₁₀ heterocyclo R_(10a)COO—R_(2a)COO— O H B2 —COX₁₀ heterocyclo R_(10a)COO— R_(2a)COO— O H B3—CONHX₁₀ heterocyclo R_(10a)COO— R_(2a)COO— O H B4 —COOX₁₀ optionallyR_(10a)COO— R_(2a)COO— O H substituted C₂ to C₈ alkyl B5 —COX₁₀optionally R_(10a)COO— R_(2a)COO— O H substituted C₂ to C₈ alkyl B6—CONHX₁₀ optionally R_(10a)COO— R_(2a)COO— O H substituted C₂ to C₈alkyl B7 —COOX₁₀ optionally R_(10a)COO— R_(2a)COO— O H substituted C₂ toC₈ alkenyl B8 —COX₁₀ optionally R_(10a)COO— R_(2a)COO— O H substitutedC₂ to C₈ alkenyl B9 —CONHX₁₀ optionally R_(10a)COO— R_(2a)COO— O Hsubstituted C₂ to C₈ alkenyl B10 —COOX₁₀ optionally R_(10a)COO—R_(2a)COO— O H substituted C₂ to C₈ alkynyl B11 —COX₁₀ optionallyR_(10a)COO— R_(2a)COO— O H substituted C₂ to C₈ alkynyl B12 —CONHX₁₀optionally R_(10a)COO— R_(2a)COO— O H substituted C₂ to C₈ alkynyl C1—COOX₁₀ heterocyclo R_(10a)COO— C₆H₅COO— R_(9a)COO— H C2 —COX₁₀heterocyclo R_(10a)COO— C₆H₅COO— R_(9a)COO— H C3 —CONHX₁₀ heterocycloR_(10a)COO— C₆H₅COO— R_(9a)COO— H C4 —COOX₁₀ optionally R_(10a)COO—C₆H₅COO— R_(9a)COO— H substituted C₂ to C₈ alkyl C5 —COX₁₀ optionallyR_(10a)COO— C₆H₅COO— R_(9a)COO— H substituted C₂ to C₈ alkyl C6 —CONHX₁₀optionally R_(10a)COO— C₆H₅COO— R_(9a)COO— H substituted C₂ to C₈ alkylC7 —COOX₁₀ optionally R_(10a)COO— C₆H₅COO— R_(9a)COO— H substituted C₂to C₈ alkenyl C8 —COX₁₀ optionally R_(10a)COO— C₆H₅COO— R_(9a)COO— Hsubstituted C₂ to C₈ alkenyl C9 —CONHX₁₀ optionally R_(10a)COO— C₆H₅COO—R_(9a)COO— H substituted C₂ to C₈ alkenyl C10 —COOX₁₀ optionallyR_(10a)COO— C₆H₅COO— R_(9a)COO— H substituted C₂ to C₈ alkynyl C11—COX₁₀ optionally R_(10a)COO— C₆H₅COO— R_(9a)COO— H substituted C₂ to C₈alkynyl C12 —CONHX₁₀ optionally R_(10a)COO— C₆H₅COO— R_(9a)COO— Hsubstituted C₂ to C₈ alkynyl D1 —COOX₁₀ heterocyclo R_(10a)COO— C₆H₅COO—OH H D2 —COX₁₀ heterocyclo R_(10a)COO— C₆H₅COO— OH H D3 —CONHX₁₀heterocyclo R_(10a)COO— C₆H₅COO— OH H D4 —COOX₁₀ optionally R_(10a)COO—C₆H₅COO— OH H substituted C₂ to C₈ alkyl D5 —COX₁₀ optionallyR_(10a)COO— C₆H₅COO— OH H substituted C₂ to C₈ alkyl D6 —CONHX₁₀optionally R_(10a)COO— C₆H₅COO— OH H substituted C₂ to C₈ alkyl D7—COOX₁₀ optionally R_(10a)COO— C₆H₅COO— OH H substituted C₂ to C₈alkenyl D8 —COX₁₀ optionally R_(10a)COO— C₆H₅COO— OH H substituted C₂ toC₈ alkenyl D9 —CONHX₁₀ optionally R_(10a)COO— C₆H₅COO— OH H substitutedC₂ to C₈ alkenyl D10 —COOX₁₀ optionally R_(10a)COO— C₆H₅COO— OH Hsubstituted C₂ to C₈ alkynyl D11 —COX₁₀ optionally R_(10a)COO— C₆H₅COO—OH H substituted C₂ to C₈ alkynyl D12 —CONHX₁₀ optionally R_(10a)COO—C₆H₅COO— OH H substituted C₂ to C₈ alkynyl E1 —COOX₁₀ heterocycloR_(10a)COO— C₆H₅COO— O OH E2 —COX₁₀ heterocyclo R_(10a)COO— C₆H₅COO— OOH E3 —CONHX₁₀ heterocyclo R_(10a)COO— C₆H₅COO— O OH E4 —COOX₁₀optionally R_(10a)COO— C₆H₅COO— O OH substituted C₂ to C₈ alkyl E5—COX₁₀ optionally R_(10a)COO— C₆H₅COO— O OH substituted C₂ to C₈ alkylE6 —CONHX₁₀ optionally R_(10a)COO— C₆H₅COO— O OH substituted C₂ to C₈alkyl E7 —COOX₁₀ optionally R_(10a)COO— C₆H₅COO— O OH substituted C₂ toC₈ alkenyl E8 —COX₁₀ optionally R_(10a)COO— C₆H₅COO— O OH substituted C₂to C₈ alkenyl E9 —CONHX₁₀ optionally R_(10a)COO— C₆H₅COO— O OHsubstituted C₂ to C₈ alkenyl E10 —COOX₁₀ optionally R_(10a)COO— C₆H₅COO—O OH substituted C₂ to C₈ alkynyl E11 —COX₁₀ optionally R_(10a)COO—C₆H₅COO— O OH substituted C₂ to C₈ alkynyl E12 —CONHX₁₀ optionallyR_(10a)COO— C₆H₅COO— O OH substituted C₂ to C₈ alkynyl F1 —COOX₁₀heterocyclo R_(10a)COO— R_(2a)COO— R_(9a)COO— H F2 —COX₁₀ heterocycloR_(10a)COO— R_(2a)COO— R_(9a)COO— H F3 —CONHX₁₀ heterocyclo R_(10a)COO—R_(2a)COO— R_(9a)COO— H F4 —COOX₁₀ optionally R_(10a)COO— R_(2a)COO—R_(9a)COO— H substituted C₂ to C₈ alkyl F5 —COX₁₀ optionally R_(10a)COO—R_(2a)COO— R_(9a)COO— H substituted C₂ to C₈ alkyl F6 —CONHX₁₀optionally R_(10a)COO— R_(2a)COO— R_(9a)COO— H substituted C₂ to C₈alkyl F7 —COOX₁₀ optionally R_(10a)COO— R_(2a)COO— R_(9a)COO— Hsubstituted C₂ to C₈ alkenyl F8 —COX₁₀ optionally R_(10a)COO— R_(2a)COO—R_(9a)COO— H substituted C₂ to C₈ alkenyl F9 —CONHX₁₀ optionallyR_(10a)COO— R_(2a)COO— R_(9a)COO— H substituted C₂ to C₈ alkenyl F10—COOX₁₀ optionally R_(10a)COO— R_(2a)COO— R_(9a)COO— H substituted C₂ toC₈ alkynyl F11 —COX₁₀ optionally R_(10a)COO— R_(2a)COO— R_(9a)COO— Hsubstituted C₂ to C₈ alkynyl F12 —CONHX₁₀ optionally R_(10a)COO—R_(2a)COO— R_(9a)COO— H substituted C₂ to C₈ alkynyl G1 —COOX₁₀heterocyclo R_(10a)COO— R_(2a)COO— OH H G2 —COX₁₀ heterocycloR_(10a)COO— R_(2a)COO— OH H G3 —CONHX₁₀ heterocyclo R_(10a)COO—R_(2a)COO— OH H G4 —COOX₁₀ optionally R_(10a)COO— R_(2a)COO— OH Hsubstituted C₂ to C₈ alkyl G5 —COX₁₀ optionally R_(10a)COO— R_(2a)COO—OH H substituted C₂ to C₈ alkyl G6 —CONHX₁₀ optionally R_(10a)COO—R_(2a)COO— OH H substituted C₂ to C₈ alkyl G7 —COOX₁₀ optionallyR_(10a)COO— R_(2a)COO— OH H substituted C₂ to C₈ alkenyl G8 —COX₁₀optionally R_(10a)COO— R_(2a)COO— OH H substituted C₂ to C₈ alkenyl G9—CONHX₁₀ optionally R_(10a)COO— R_(2a)COO— OH H substituted C₂ to C₈alkenyl G10 —COOX₁₀ optionally R_(10a)COO— R_(2a)COO— OH H substitutedC₂ to C₈ alkynyl G11 —COX₁₀ optionally R_(10a)COO— R_(2a)COO— OH Hsubstituted C₂ to C₈ alkynyl G12 —CONHX₁₀ optionally R_(10a)COO—R_(2a)COO— OH H substituted C₂ to C₈ alkynyl H1 —COOX₁₀ heterocycloR_(10a)COO— C₆H₅COO— OH OH H2 —COX₁₀ heterocyclo R_(10a)COO— C₆H₅COO— OHOH H3 —CONHX₁₀ heterocyclo R_(10a)COO— C₆H₅COO— OH OH H4 —COOX₁₀oprionally R_(10a)COO— C₆H₅COO— OH OH substituted C₂ to C₈ alkyl H5—COX₁₀ optionally R_(10a)COO— C₆H₅COO— OH OH substituted C₂ to C₈ alkylH6 —CONHX₁₀ optionally R_(10a)COO— C₆H₅COO— OH OH substituted C₂ to C₈alkyl H7 —COOX₁₀ optionally R_(10a)COO— C₆H₅COO— OH OH substituted C₂ toC₈ alkenyl H8 —COX₁₀ optionally R_(10a)COO— C₆H₅COO— OH OH substitutedC₂ to C₈ alkenyl H9 —CONHX₁₀ optionally R_(10a)COO— C₆H₅COO— OH OHsubstituted C₂ to C₈ alkenyl H10 —COOX₁₀ optionally R_(10a)COO— C₆H₅COO—OH OH substituted C₂ to C₈ alkynyl H11 —COX₁₀ optionally R_(10a)COO—C₆H₅COO— OH OH substituted C₂ to C₈ alkynyl H12 —CONHX₁₀ optionallyR_(10a)COO— C₆H₅COO— OH OH substituted C₂ to C₈ alkynyl I1 —COOX₁₀heterocyclo R_(10a)COO— R_(2a)COO— O OH I2 —COX₁₀ heterocycloR_(10a)COO— R_(2a)COO— O OH I3 —CONHX₁₀ heterocyclo R_(10a)COO—R_(2a)COO— O OH I4 —COOX₁₀ optionally R_(10a)COO— R_(2a)COO— O OHsubstituted C₂ to C₈ alkyl I5 —COX₁₀ optionally R_(10a)COO— R_(2a)COO— OOH substituted C₂ to C₈ alkyl I6 —CONHX₁₀ optionally R_(10a)COO—R_(2a)COO— O OH substituted C₂ to C₈ alkyl I7 —COOX₁₀ optionallyR_(10a)COO— R_(2a)COO— O OH substituted C₂ to C₈ alkenyl I8 —COX₁₀optionally R_(10a)COO— R_(2a)COO— O OH substituted C₂ to C₈ alkenyl I9—CONHX₁₀ optionally R_(10a)COO— R_(2a)COO— O OH substituted C₂ to C₈alkenyl I10 —COOX₁₀ optionally R_(10a)COO— R_(2a)COO— O OH substitutedC₂ to C₈ alkynyl I11 —COX₁₀ optionally R_(10a)COO— R_(2a)COO— O OHsubstituted C₂ to C₈ alkynyl I12 —CONHX₁₀ optionally R_(10a)COO—R_(2a)COO— O OH substituted C₂ to C₈ alkynyl J1 —COOX₁₀ heterocycloR_(10a)COO— R_(2a)COO— OH OH J2 —COX₁₀ heterocyclo R_(10a)COO—R_(2a)COO— OH OH J3 —CONHX₁₀ heterocyclo R_(10a)COO— R_(2a)COO— OH OH J4—COOX₁₀ optionally R_(10a)COO— R_(2a)COO— OH OH substituted C₂ to C₈alkyl J5 —COX₁₀ optionally R_(10a)COO— R_(2a)COO— OH OH substituted C₂to C₈ alkyl J6 —CONHX₁₀ optionally R_(10a)COO— R_(2a)COO— OH OHsubstituted C₂ to C₈ alkyl J7 —COOX₁₀ optionally R_(10a)COO— R_(2a)COO—OH OH substituted C₂ to C₈ alkenyl J8 —COX₁₀ optionally R_(10a)COO—R_(2a)COO— OH OH substituted C₂ to C₈ alkenyl J9 —CONHX₁₀ optionallyR_(10a)COO— R_(2a)COO— OH OH substituted C₂ to C₈ alkenyl J10 —COOX₁₀optionally R_(10a)COO— R_(2a)COO— OH OH substituted C₂ to C₈ alkynyl J11—COX₁₀ optionally R_(10a)COO— R_(2a)COO— OH OH substituted C₂ to C₈alkynyl J12 —CONHX₁₀ optionally R_(10a)COO— R_(2a)COO— OH OH substitutedC₂ to C₈ alkynyl K1 —COOX₁₀ heterocyclo R_(10a)COO— R_(2a)COO—R_(9a)COO— OH K2 —COX₁₀ heterocyclo R_(10a)COO— R_(2a)COO— R_(9a)COO— OHK3 —CONHX₁₀ heterocyclo R_(10a)COO— R_(2a)COO— R_(9a)COO— OH K4 —COOX₁₀optionally R_(10a)COO— R_(2a)COO— R_(9a)COO— OH substituted C₂ to C₈alkyl K5 —COX₁₀ optionally R_(10a)COO— R_(2a)COO— R_(9a)COO— OHsubstituted C₂ to C₈ alkyl K6 —CONHX₁₀ optionally R_(10a)COO— R_(2a)COO—R_(9a)COO— OH substituted C₂ to C₈ alkyl K7 —COOX₁₀ optionallyR_(10a)COO— R_(2a)COO— R_(9a)COO— OH substituted C₂ to C₈ alkenyl K8—COX₁₀ optionally R_(10a)COO— R_(2a)COO— R_(9a)COO— OH substituted C₂ toC₈ alkenyl K9 —CONHX₁₀ optionally R_(10a)COO— R_(2a)COO— R_(9a)COO— OHsubstituted C₂ to C₈ alkenyl K10 —COOX₁₀ optionally R_(10a)COO—R_(2a)COO— R_(9a)COO— OH substituted C₂ to C₈ alkynyl K11 —COX₁₀optionally R_(10a)COO— R_(2a)COO— R_(9a)COO— OH substituted C₂ to C₈alkynyl K12 —CONHX₁₀ optionally R_(10a)COO— R_(2a)COO— R_(9a)COO— OHsubstituted C₂ to C₈ alkynyl

Example 5

[0104] In Vitro cytotoxicity measured by the cell colony formation assay

[0105] Four hundred cells (HCT116) were plated in 60 mm Petri dishescontaining 2.7 mL of medium (modified McCoy's 5a medium containing 10%fetal bovine serum and 100 units/mL penicillin and 100 g/mLstreptomycin). The cells were incubated in a CO₂ incubator at 37° C. for5 h for attachment to the boftom of Petri dishes. The compoundsidentified in Example 2 were made up fresh in medium at ten times thefinal concentration, and then 0.3 mL of this stock solution was added tothe 2.7 mL of medium in the dish. The cells were then incubated withdrugs for 72 h at 37° C. At the end of incubation the drug-containingmedia were decanted, the dishes were rinsed with 4 mL of Hank's BalanceSalt Solution (HBSS), 5 mL of fresh medium was added, and the disheswere returned to the incubator for colony formation. The cell colonieswere counted using a colony counter after incubation for 7 days. Cellsurvival was calculated and the values of ID50 (the drug concentrationproducing 50% inhibition of colony formation) were determined for eachtested compound. IN VITRO Compound ID 50 (nm) HCT116 taxol 2.1 docetaxel0.6 6577 <1 6515 <1 6066 <1 6111 <1

1. A taxane having the formula:

wherein R₂ is acyloxy; R₇ is hydroxy; R₉ is keto, hydroxy, or acyloxy;R₁₀ is heterosubstituted acetate;; R₁₄ is hydrido or hydroxy; X₃ issubstituted or unsubstituted alkyl, alkenyl, alkynyl, phenyl orheterocyclo; X₅ is —COX₁₀, —COOX₁₀, or —CONHX₁₀; X₁₀ is hydrocarbyl,substituted hydrocarbyl, or heterocyclo; and Ac is acetyl:
 2. The taxaneof claim 1 wherein X₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, C₁- C₈ alkyl, C₂-C₈ alkenyl, or C₂- C₈alkynyl.
 3. The taxane of claim 1 wherein X₅ is —COX₁₀ and X₁₀ issubstituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl,3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁- C₈ alkyl, C₂- C₈alkenyl, or C₂- C₈ alkynyl, or X₅ is —COOX₁₀ and X₁₀ is substituted orunsubstituted C₁- C₈ alkyl, C₂- C₈ alkenyl, or C₂-C₈ alkynyl.
 4. Thetaxane of claim 1 wherein X₅ is —COX₁₀ and X₁₀ is phenyl, or X₅ is—COOX₁₀ and X₁₀ is t-butyl.
 5. The taxane of claim 1 wherein R₁₄ ishydrido.
 6. The taxane of claim 5 wherein X₃ is 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁- C₈ alkyl, C₂-C₈ alkenyl, or C₂- C₈ alkynyl.
 7. The taxane of claim 5 wherein X₅ is—COX₁₀ and X₁₀ is substituted or unsubstituted phenyl, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁- C₈ alkyl, C₂-C₈ alkenyl, or C₂- C₈ alkynyl or X₅ is —COOX₁₀ and X₁₀ is substituted orunsubstituted C₁- C₈ alkyl, C₂- C₈ alkenyl, or C₂-C₈ alkynyl.
 8. Thetaxane of claim 5 wherein X₅ is —COX₁₀ and X₁₀ is phenyl, or X₅ is—COOX₁₀ and X₁₀ is t-butyl.
 9. The taxane of claim 5 wherein X₃ isphenyl.
 10. The taxane of claim 1 wherein R₂ is benzoyloxy.
 11. Thetaxane of claim 10 wherein X₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, C₁- C₈ alkyl, C₂- C₈ alkenyl, or C₂- C₈alkynyl.
 12. The taxane of claim 10 wherein X₅ is —COX₁₀ and X₁₀ issubstituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl,3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁- C₈ alkyl, C₂- C₈alkenyl, or C₂- C₈ alkynyl or X₅ is —COOX₁₀ and X₁₀ is substituted orunsubstituted C₁- C₈ alkyl, C₂- C₈ alkenyl, or C₂- C₈ alkynyl.
 13. Thetaxane of claim 10 wherein X₅ is —COX₁₀ and X₁₀ is phenyl, or X₅ is—COOX₁₀ and X₁₀ is t-butyl.
 14. The taxane of claim 10 wherein X₃ isphenyl.
 15. The taxane of claim 1 wherein R₁₄ is hydrido and R₉ is keto.16. The taxane of claim 15 wherein X₃ is 2-furyl, 3-furyl, 2-thienyl,3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁- C₈ alkyl, C₂- C₈alkenyl, or C₂- C₈ alkynyl.
 17. The taxane of claim 15 wherein X₅ is—COX₁₀ and X₁₀ is substituted or unsubstituted phenyl, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁- C₈ alkyl, C₂-C₈ alkenyl, or C₂- C₈ alkynyl or X₅ is —COOX₁₀ and X₁₀ is substituted orunsubstituted C₁- C₈ alkyl, C₂- C₈ alkenyl, or C₂- C₈ alkynyl.
 18. Thetaxane of claim 15 wherein X₅ is —COX₁₀ and X₁₀ is phenyl, or X₅ is—COOX₁₀ and X₁₀ is t-butyl.
 19. The taxane of claim 15 wherein X₃ isphenyl, and X₅ is —COX₁₀ wherein X₁₀ is phenyl, or X₅ is —COOX₁₀ whereinX₁₀ is t-butyl.
 20. The taxane of claim 1 wherein R₂ is benzoyloxy andR₉ is keto.
 21. The taxane of claim 20 wherein X₃ is 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁- C₈ alkyl, C₂-C₈ alkenyl, or C₂- C₈ alkynyl.
 22. The taxane of claim 20 wherein X₅ is—COX₁₀ and X₁₀ is substituted or unsubstituted phenyl, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl,C₂-C₈ alkenyl, or C₂-C₈ alkynyl or X₅ is —COOX₁₀ and X₁₀ is substitutedor unsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.
 23. Thetaxane of claim 20 wherein X₅ is —COX₁₀ and X₁₀ is phenyl, or X₅ is—COOX₁₀ and X₁₀ is t-butyl.
 24. The taxane of claim 20 wherein X₃ isphenyl, and X₅ is —COX₁₀ wherein X₁₀ is phenyl, or X₅ is —COOX₁₀ whereinX₁₀ is t-butyl.
 25. The taxane of claim 1 wherein R₁₄ is hydrido and R₂is benzoyloxy.
 26. The taxane of claim 25 wherein X₃ is 2-furyl,3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.
 27. The taxane of claim 25wherein X₅ is —COX₁₀ and X₁₀ is substituted or unsubstituted phenyl,2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl or X₅ is —COOX₁₀ and X₁₀ issubstituted or unsubstituted C₁- C₈ alkyl, C₂- C₈ alkenyl, or C₂- C₈alkynyl.
 28. The taxane of claim 25 wherein X₅ is —COX₁₀ and X₁₀ isphenyl, or X₅ is —COOX₁₀ and X₁₀ is t-butyl.
 29. The taxane of claim 25wherein X₃ is phenyl, and X₅ is —COX₁₀ wherein X₁₀ is phenyl, or X₅ is—COOX₁₀ wherein X₁₀ is t-butyl.
 30. The taxane of claim 1 wherein R₁₄ ishydrido, R₉ is keto, and R₂ is benzoyloxy.
 31. The taxane of claim 30wherein X₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl. 32.The taxane of claim 30 wherein X₅ is —COX₁₀ and X₁₀ is substituted orunsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl or X₅is —COOX₁₀ and X₁₀ is substituted or unsubstituted C₁-C₈ alkyl, C₂-C₈alkenyl, or C₂-C₈ alkynyl.
 33. The taxane of claim 30 wherein X₅ is—COX₁₀ and X₁₀ is phenyl, or X₅ is —COOX₁₀ and X₁₀ is t-butyl.
 34. Thetaxane of claim 30 wherein X₃ iS phenyl, and X₅ is —COX₁₀ wherein X₁₀ isphenyl, or X₅ is —COOX₁₀ wherein X₁₀ is t-butyl.
 35. The taxane of claim30 wherein X₅ is —COOX₁₀ and X₁₀ is t-butyl.
 36. The taxane of claim 35wherein X₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, cycloalkyl, alkenyl, or phenyl.
 37. The taxane ofclaim 35 wherein X₃ is furyl or thienyl.
 38. The taxane of claim 35wherein X₃ is cycloalkyl.
 39. The taxane of claim 1 wherein R₁₀ isR_(10a)COO— and R_(10a) is heterocyclo, alkoxy, alkenoxy, alkynoxy,aryloxy, hydroxy, protected hydroxy, oxy, acyloxy, nitro, amino, amido,thiol, ketal, acetal, ester or ether.
 40. The taxane of claim 39 whereinR_(10a) is heterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, oracyloxy.
 41. The taxane of claim 39 wherein R_(10a) is alkoxy, alkenoxy,aryloxy, hydroxy, or acyloxy.
 42. A taxane having the formula

R₇ is hydroxy; R₁₀ is R_(10a)COO—; R_(10a) is heterosubstituted methyl,said heterosubstituted methyl moiety lacking a carbon atom which is inthe beta position relative to the carbon of which R_(10a) is asubstituent; X₃ is substituted or unsubstituted alkyl, alkenyl, alkynyl,phenyl or heterocyclo; X₅ is —COX₁₀, —COOX₁₀, or —CONHX₁₀; and X₁₀ ishydrocarbyl, substituted hydrocarbyl, or heterocyclo.
 43. The taxane ofclaim 42 wherein X₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈alkynyl.
 44. The taxane of claim 43 wherein X₅ is —COX₁₀ and X₁₀ issubstituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl,3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl,or C₂-C₈ alkynyl, or X₅ is —COOX₁₀ and X₁₀ is substituted orunsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.
 45. Thetaxane of claim 43 wherein R₁₀ is R_(10a)COO— and R_(10a) isheterocyclo, alkoxy, alkenoxy, alkynoxy, aryloxy, hydroxy, protectedhydroxy, oxy, acyloxy, nitro, amino, amido, thiol, ketal, acetal, esteror ether, and X₅ is —COX₁₀ wherein X₁₀ is phenyl, or X₅ is —COOX₁₀wherein X₁₀ is t-butyl.
 46. The taxane of claim 43 wherein R₁₀ isR_(10a)COO— and R_(10a) is alkoxy, alkenoxy, aryloxy, hydroxy, acyloxy,ester or ether, and X₅ is —COX₁₀ wherein X₁₀ is phenyl, or X₅ is —COOX₁₀wherein X₁₀ is t-butyl.
 47. The taxane of claim 43 wherein R₁₀ isR_(10a)COO— and R_(10a) is alkoxy, or aryloxy, and X₅ is —COX₁₀ whereinX₁₀ is phenyl, or X₅ is —COOX₁₀ wherein X₁₀ is t-butyl.
 48. The taxaneof claim 43 wherein X₅ is —COX₁₀ and X₁₀ is phenyl, or X₅ is —COOX₁₀ andX₁₀ is t-butyl.
 49. The taxane of claim 42 wherein X₃ is furyl orthienyl.
 50. The taxane of claim 49 wherein X₅ is —COX₁₀ and X₁₀ issubstituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl,3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl,or C₂-C₈ alkynyl, or X₅ is —COOX₁₀ and X₁₀ is substituted orunsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.
 51. Thetaxane of claim 49 wherein X₅ is —COX₁₀ and X₁₀ is phenyl, or X₅ is—COOX₁₀ and X₁₀ is t-butyl.
 52. The taxane of claim 43 wherein X₃ iscycloalkyl.
 53. The taxane of claim 52 wherein X₅ is —COX₁₀ and X₁₀ issubstituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl,3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl,or C₂-C₈ alkynyl, or X₅ iS —COOX₁₀ and X₁₀ is substituted orunsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.
 54. Thetaxane of claim 52 wherein X₅ is —COX₁₀ and X₁₀ is phenyl, or X₅ is—COOX₁₀ and X₁₀ is t-butyl.
 55. The taxane of claim 43 wherein X₃ isisobutenyl.
 56. The taxane of claim 55 wherein X₅ is —COX₁₀ and X₁₀ issubstituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl,3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl C₁-C₈ alkyl, C₂-C₈ alkenyl,or C₂-C₈ alkynyl, or X₅ is —COOX₁₀ and X₁₀ is substituted orunsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.
 57. Thetaxane of claim 55 wherein X₅ is —COX₁₀ and X₁₀ is phenyl, or X₅ is—COOX₁₀ and X₁₀ is t-butyl.
 58. The taxane of claim 42 wherein R₁₀ isalkoxyacetyl or acyloxyacetyl.
 59. The taxane of claim 58 wherein X₃ isfuryl, thienyl, pyridyl, alkyl, alkenyl, or phenyl.
 60. The taxane ofclaim 59 wherein X₅ is —COX₁₀ and X₁₀ is substituted or unsubstitutedphenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl,4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl, or X₅ is—COOX₁₀ and X₁₀ is substituted or unsubstituted C₁-C₈ alkyl, C₂-C₈alkenyl, or C₂-C₈ alkynyl.
 61. The taxane of claim 59 wherein X₅ is—COX₁₀ and X₁₀ is phenyl, or X₅ is —COOX₁₀ and X₁₀ is t-butyl.
 62. Thetaxane of claim 58 wherein X₃ is cycloalkyl.
 63. The taxane of claim 62wherein X₅ is —COX₁₀ and X₁₀ is substituted or unsubstituted phenyl,2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl, or X₅ is —COOX₁₀ and X₁₀is substituted or unsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈alkynyl.
 64. The taxane of claim 62 wherein X₅ is —COX₁₀ and X₁₀ isphenyl, or X₅ is —COOX₁₀ and X₁₀ is t-butyl.
 65. The taxane of claim 58wherein X₃ is phenyl.
 66. The taxane of claim 65 wherein X₅ is —COX₁₀and X₁₀ is substituted or unsubstituted phenyl, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl,C₂-C₈ alkenyl, or C₂-C₈ alkynyl, or X₅ is —COOX₁₀ and X₁₀ is substitutedor unsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.
 67. Thetaxane of claim 65 wherein X₅ is —COX₁₀ and X₁₀ is phenyl, or X₅ is—COOX₁₀ and X₁₀ is t-butyl.
 68. The taxane of claim 42 wherein X₃ isfuryl or thienyl, and X₅ iS —COX₁₀ wherein X₁₀ is phenyl, or X₅ is—COOX₁₀ wherein X₁₀ is t-butyl.
 69. The taxane of claim 42 wherein X₃ issubstituted or unsubstituted furyl, and X₅ is —COX₁₀ wherein X₁₀ isphenyl, or X₅ is —COOX₁₀ wherein X₁₀ is t-butyl.
 70. The taxane of claim42 wherein X₃ is substituted or unsubstituted thienyl, and X₅ is —COX₁₀wherein X₁₀ is phenyl, or X₅ is —COOX₁₀ wherein X₁₀ is t-butyl.
 71. Thetaxane of claim 42 wherein X₃ is isobutenyl, and X₅ is —COX₁₀ and X₁₀ isphenyl, or X₅ is —COOX₁₀ and X₁₀ is t-butyl.
 72. The taxane of claim 42wherein X₃ is alkyl, and X₅ is —COX₁₀ and X₁₀ is phenyl, or X₅ is—COOX₁₀ and X₁₀ is t-butyl.
 73. The taxane of claim 42 wherein X₃ isfuryl, thienyl or phenyl, X₅ is —COOX₁₀ and X₁₀ is t-butyl
 74. Thetaxane of claim 42 wherein X₃ is isobutenyl or cycloalkyl, X₅ is —COOX₁₀and X₁₀ is t-butyl.
 75. A pharmaceutical composition comprising thetaxane of claim 1 and at least one pharmaceutically acceptable carrier.76. The pharmaceutical composition of claim 75 wherein X₃ is 2-furyl,3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, phenyl or substituted phenyl. 77.The pharmaceutical composition of claim 76 wherein X₅ is —COX₁₀ and X₁₀is substituted or unsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl,3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl,or C₂-C₈ alkynyl, or X₅ is —COOX₁₀ and X₁₀ is substituted orunsubstituted C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl.
 78. Thepharmaceutical composition of claim 76 wherein X₅ is —COX₁₀ and X₁₀ isphenyl, or X₅ is —COOX₁₀ and X₁₀ is t-butyl.
 79. The pharmaceuticalcomposition of claim 76 wherein X₃ is substituted or unsubstituted furylor thienyl, and X₅ is —COX₁₀ wherein X₁₀ is phenyl, or X₅ is —COOX₁₀ andX₁₀ is t-butyl.
 80. The pharmaceutical composition of claim 76 whereinX₃ is furyl or thienyl, and X₅ is —COX₁₀ wherein X₁₀ is phenyl, or X₅ is—COOX₁₀ wherein X₁₀ is t-butyl.
 81. The pharmaceutical composition ofclaim 76 wherein X₃ is alkyl or isobutenyl, and X₅ is —COX₁₀ wherein X₁₀is phenyl, or X₅ is —COOX₁₀ wherein X₁₀ is t-butyl.
 82. Thepharmaceutical composition of claim 76 wherein X₃ is furyl or thienyl,X₅ is —COOX₁₀ and X₁₀ is t-butyl.
 83. The pharmaceutical composition ofclaim 76 wherein X₃ is isobutenyl or alkyl, X₅ is —COOX₁₀ and X₁₀ ist-butyl.
 84. A pharmaceutical composition comprising the taxane of claim42 and at least one pharmaceutically acceptable carrier.
 85. Apharmaceutical composition comprising the taxane of claim 49 and atleast one pharmaceutically acceptable carrier.
 86. A composition fororal administration comprising the taxane of claim 1 and at least onepharmaceutically acceptable carrier.
 87. The pharmaceutical compositionof claim 86 wherein X₃ is 2-furyl, 3-furyl, 2-thienyl, 3-thienyl,2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, C₂-C₈alkynyl, phenyl or substituted phenyl.
 88. The pharmaceuticalcomposition of claim 87 wherein X₅ is —COX₁₀ and X₁₀ is substituted orunsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl, orX₅ is —COOX₁₀ and X₁₀ is substituted or unsubstituted C₁ - C₈ alkyl,C₂-C₈ alkenyl, or C₂-C₈ alkynyl.
 89. The pharmaceutical composition ofclaim 87 wherein X₅ is —COX₁₀ and X₁₀ is phenyl, or X₅ is —COOX₁₀ andX₁₀ is t-butyl.
 90. The pharmaceutical composition of claim 87 whereinX₃ is substituted or unsubstituted furyl or thienyl, and X₅ is —COX₁₀wherein X₁₀ is phenyl, or X₅ is —COOX₁₀ and X₁₀ is t-butyl.
 91. Acomposition for oral administration comprising the taxane of claim 42and at least one pharmaceutically acceptable carrier.
 92. A compositionfor oral administration comprising the taxane of claim 49 and at leastone pharmaceutically acceptable carrier.
 93. A method of inhibitingtumor growth in a mammal, said method comprising orally administering atherapeutically effective amount of a pharmaceutical compositioncomprising the taxane of claim 1 and at least one pharmaceuticallyacceptable carrier.
 94. The method of claim 93 wherein X₃ is 2-furyl,3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C₁-C₈alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, phenyl or substituted phenyl. 95.The method of claim 94 wherein X₅ is —COX₁₀ and X₁₀ is substituted orunsubstituted phenyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl,3-pyridyl, 4-pyridyl, C₁-C₈ alkyl, C₂-C₈ alkenyl, or C₂-C₈ alkynyl, orX₅ is —COOX₁₀ and X₁₀ is substituted or unsubstituted C₁-C₈ alkyl, C₂-C₈alkenyl, or C₂-C₈ alkynyl.
 96. The method of claim 94 wherein X₅ is—COX₁₀ and X₁₀ is phenyl, or X₅ is —COOX₁₀ and X₁₀ is t-butyl.
 97. Themethod of claim 94 wherein X₃ is substituted or unsubstituted furyl orthienyl, and X₅ is -COX₁₀ wherein X₁₀ is phenyl, or X₅ is —COOX₁₀ andX₁₀ is t-butyl.
 98. A method of inhibiting tumor growth in a mammal,said method comprising orally administering a therapeutically effectiveamount of a pharmaceutical composition comprising the taxane of claim 42and at least one pharmaceutically acceptable carrier.
 99. A method ofinhibiting tumor growth in a mammal, said method comprising orallyadministering a therapeutically effective amount of a pharmaceuticalcomposition comprising the taxane of claim 49 and at least onepharmaceutically acceptable carrier.